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1.
Int Immunol ; 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39320393

RESUMO

Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ PD-1+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant proinflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions including autoimmunity and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, autoimmune and chronic inflammatory diseases and provides a novel therapeutic clue.

2.
J Cell Physiol ; 239(9): e31396, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39104026

RESUMO

RECK is a candidate tumor suppressor gene isolated as a gene that induces flat reversion in a cell line transformed by the KRAS oncogene. Since RECK knockout mice die in utero, they are not suitable for studying the effects of RECK on tumor formation. In this study, we found an increased incidence of spontaneous pulmonary adenomas in mice with reduced RECK expression (RECK-Hypo mice). To evaluate the effects of RECK expressed by either tumor cells or host cells on tumor growth, we established a tumorigenic cell line (MKER) from the kidney of a C57BL/6 mouse and performed syngeneic transplantation experiments. Our results indicate that when RECK expression is low in host cells, transplanted MKER cells grow faster and kill the animal more rapidly. Since RECK is required for the formation of proper fibrillin fibers that serve as a tissue reservoir for precursors of TGFß-family cytokines, we assessed the levels of TGFß1 in the peripheral blood. We found a significant increase in TGFß1 in RECK-Hypo mice compared to wild-type mice. We also found that the proportion of FOXP3-positive regulatory T (Treg) cells among splenocytes was higher in RECK-Hypo mice compared to the control mice. Furthermore, the number of FOXP3-positive cells in spontaneous hematopoietic neoplasms in the lungs as well as tumors that formed after MKER transplantation was significantly higher in RECK-Hypo mice compared to the control mice. These findings indicate that RECK-mediated tumor suppression involves a non-cell-autonomous mechanism and that possible roles of TGFß1 and Treg cells in such a mechanism warrant further study.


Assuntos
Proteínas Ligadas por GPI , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores , Animais , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/genética , Linfócitos T Reguladores/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Camundongos , Linhagem Celular Tumoral , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Proliferação de Células , Adenoma/patologia , Adenoma/genética , Adenoma/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Camundongos Knockout
3.
Immunity ; 41(5): 753-61, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25464854

RESUMO

Medullary thymic epithelial cells (mTECs) are crucial for central T cell self-tolerance. Although progenitors of mTECs have been demonstrated in thymic organogenesis, the mechanism for postnatal mTEC maintenance remains elusive. We demonstrate that implantation of embryonic TECs expressing claudin-3 and claudin-4 (Cld3,4) in a medulla-defective thymic microenvironment restores medulla formation and suppresses multiorgan autoimmunity throughout life. A minor SSEA-1(+) fraction within the embryonic Cld3,4(hi) TECs contained self-renewable clonogenic TECs, capable of preferentially generating mature mTECs in vivo. Adult SSEA-1(+)Cld3,4(hi) TECs retained mTEC reconstitution potential, although the activity decreased. The clonogenicity of TECs also declined rapidly after birth in wild-type mice, whereas it persisted in Rag2(?/?) adult mice with defective thymopoiesis. The results suggest that unipotent mTEC-restricted stem cells that develop in the embryo have the capacity to functionally reconstitute the thymic medulla long-term, thus ensuring lifelong central T cell self-tolerance.


Assuntos
Organogênese/imunologia , Tolerância a Antígenos Próprios/imunologia , Células-Tronco/imunologia , Linfócitos T/imunologia , Timo/citologia , Animais , Antígenos Glicosídicos Associados a Tumores/biossíntese , Diferenciação Celular/imunologia , Células Cultivadas , Claudina-3/biossíntese , Claudina-4/biossíntese , Proteínas de Ligação a DNA/genética , Células Epiteliais/citologia , Células Epiteliais/imunologia , Antígenos CD15/biossíntese , Camundongos , Camundongos Knockout , Antígenos Embrionários Estágio-Específicos/biossíntese , Células-Tronco/citologia , Timo/imunologia
4.
Int Immunol ; 33(3): 171-182, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038259

RESUMO

T-cell development depends on the thymic microenvironment, in which endothelial cells (ECs) play a vital role. Interestingly, vascular permeability of the thymic cortex is lower than in other organs, suggesting the existence of a blood-thymus barrier (BTB). On the other hand, blood-borne molecules and dendritic cells bearing self-antigens are accessible to the medulla, facilitating central tolerance induction, and continuous T-precursor immigration and mature thymocyte egress occur through the vessels at the cortico-medullary junction (CMJ). We found that claudin-5 (Cld5), a membrane protein of tight junctions, was expressed in essentially all ECs of the cortical vasculatures, whereas approximately half of the ECs of the medulla and CMJ lacked Cld5 expression. An intravenously (i.v.) injected biotin tracer hardly penetrated cortical Cld5+ vessels, but it leaked into the medullary parenchyma through Cld5- vessels. Cld5 expression in an EC cell line caused a remarkable increase in trans-endothelial resistance in vitro, and the biotin tracer leaked from the cortical vasculatures in Cldn5-/- mice. Furthermore, i.v.-injected sphingosine-1 phosphate distributed selectively into the medulla through the Cld5- vessels, probably ensuring the egress of CD3high mature thymocytes from Cld5- vessels at the CMJ. These results suggest that distinct Cld5 expression profiles in the cortex and medulla may control the BTB and the T-cell gateway to blood circulation, respectively.


Assuntos
Permeabilidade Capilar/fisiologia , Claudina-5/metabolismo , Linfócitos T/metabolismo , Timo/metabolismo , Junções Íntimas/fisiologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular , Claudina-5/biossíntese , Células Endoteliais/metabolismo , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Linfócitos T/citologia , Timócitos/metabolismo
5.
J Immunol ; 205(8): 2008-2015, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32907997

RESUMO

Immune complexes (ICs) in blood are efficiently removed mainly by liver reticuloendothelial systems consisting of sinusoidal endothelial cells and Kupffer cells expressing FcγR. The bone marrow (BM) also has sinusoidal vasculatures, and sinusoidal BM endothelial cells (BMECs) bear unique function, including hematopoietic niches and traffic regulation of hematopoietic cells. In this study, we found that sinusoidal BMECs express FcγRIIb2, which is markedly increased in anemic conditions or by the administration of erythropoietin (Epo) in healthy mice. BMECs expressed Epo receptor (EpoR), and the Epo-induced increase in FcγRIIb2 expression was abolished in Epor-/- ::HG1-Epor transgenic mice, which lack EpoR in BMECs except for BM erythroblasts, suggesting the effect was directly mediated via EpoR on BMECs. Further, although BMECs hardly captured i.v.-injected soluble ICs in healthy mice, Epo administration induced a remarkable increase in the uptake of ICs in a FcγRIIb-dependent manner. Enhancement of the IC incorporation capacity by Epo was also observed in cultured BMECs in vitro, suggesting the direct effect of Epo on BMECs. Moreover, we found that i.v.-injected ICs in Epo-treated mice were more rapidly removed from the circulation than in PBS-treated mice. These results reveal a novel function of BMECs to efficiently remove circulating blood-borne ICs in an FcγRIIb2-mediated manner.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Células da Medula Óssea/imunologia , Células Endoteliais/imunologia , Eritropoetina/imunologia , Receptores de IgG/imunologia , Animais , Complexo Antígeno-Anticorpo/sangue , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Eritropoetina/sangue , Eritropoetina/genética , Camundongos , Camundongos Knockout , Receptores de IgG/sangue , Receptores de IgG/genética
6.
Nature ; 534(7607): 402-6, 2016 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-27281199

RESUMO

Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR). Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.


Assuntos
Regiões 3' não Traduzidas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Receptor de Morte Celular Programada 1/genética , Evasão Tumoral/genética , Regulação para Cima , Adenocarcinoma/genética , Animais , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Seleção Clonal Mediada por Antígeno , Feminino , Marcadores Genéticos/genética , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Linfoma Difuso de Grandes Células B/genética , Camundongos , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/biossíntese , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética
7.
Int Immunol ; 32(4): 223-231, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-31967307

RESUMO

Acquired immune function shows recognizable changes over time with organismal aging. These changes include T-cell dysfunction, which may underlie diminished resistance to infection and possibly various chronic age-associated diseases in the elderly. T-cell dysfunction may occur at distinct stages, from naive cells to the end stages of differentiation during immune responses. The thymus, which generates naive T cells, shows unusually early involution resulting in progressive reduction of T-cell output after adolescence, but peripheral T-cell numbers are maintained through antigen-independent homeostatic proliferation of naive T cells driven by the major histocompatibility complex associated with self-peptides and homeostatic cytokines, retaining the diverse repertoire. However, extensive homeostatic proliferation may lead to the emergence of dysfunctional CD4+ T cells with features resembling senescent cells, termed senescence-associated T (SA-T) cells, which increase and accumulate with age. In situations such as chronic viral infection, T-cell dysfunction may also develop via persistent antigen stimulation, termed exhaustion, preventing possible immunopathology due to excessive immune responses. Exhausted T cells are developed through the effects of checkpoint receptors such as PD-1 and may be reversed with the receptor blockade. Of note, although defective in their regular T-cell antigen-receptor-mediated proliferation, SA-T cells secrete abundant pro-inflammatory factors such as osteopontin, reminiscent of an SA-secretory phenotype. A series of experiments in mouse models indicated that SA-T cells are involved in systemic autoimmunity as well as chronic tissue inflammation following tissue stresses. In this review, we discuss the physiological aspects of T-cell dysfunction associated with aging and its potential pathological involvement in age-associated diseases and possibly cancer.


Assuntos
Senescência Celular/imunologia , Linfócitos T/imunologia , Animais , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/patologia
8.
J Immunol ; 203(1): 167-177, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31085589

RESUMO

Mainstream CD8+ and CD4+ T cells of αß lineage are developed in the thymus through TCR-mediated selection in the context of MHC class I and MHC class II in association with self-peptides, respectively. In addition, minor αßT cells bearing invariant TCRs, NKT cells, and mucosal-associated invariant T cells are selected via MHC-like molecules, CD1d, and MR1 complexed with nonpeptide Ags, respectively, parts of which express neither CD4 nor CD8. In this study, we indicate that bone marrow (BM), but barely other lymphoid tissues, harbors CD4/CD8 double-negative αßT cells with an apparently diverse TCR repertoire at considerable proportions in healthy adult mice. The BM-resident double-negative αßT (BMDNT) cells are developed in the thymus in a Notch and IL-7-dependent manner but independently of known restriction elements, including MHC class I, MHC class II, CD1d, and MR1. These cells are sustained in BM throughout the adult stage with "homeostatic" proliferation via IL-1ß derived from normal myeloid cells dominating the BM environment. Although BMDNT cells secrete a unique set of cytokines, including IL-17, GM-CSF, IL-3, and CCL chemokines on TCR stimulation, these T cells also express a series of NK receptors and exhibit a potent NK-like cytotoxic activity. Furthermore, BMDNT cells show robustly accelerated proliferation and activation following systemic administration of TLR ligands likely through the enhanced production of IL-1ß by myeloid cells in situ. Our results suggest that αßT lineage cells that are developed in the thymus by default of TCR-mediated selection are maintained and differentiated to innate-like T cells in BM and may play a role in innate immunity in the hematopoietic environment.


Assuntos
Medula Óssea/fisiologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/imunologia , Timo/fisiologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Citotoxicidade Imunológica , Homeostase , Imunidade Inata , Interleucina-1beta/metabolismo , Interleucina-7/genética , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout
9.
Int Immunol ; 31(3): 127-139, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30534943

RESUMO

Hassall's corpuscles (HCs) are composed of cornifying, terminally differentiated medullary thymic epithelial cells (mTECs) that are developed under the control of Aire. Here, we demonstrated that HC-mTECs show features of cellular senescence and produce inflammatory cytokines and chemokines including CXCL5, thereby recruiting and activating neutrophils to produce IL-23 in the thymic medulla. We further indicated that thymic plasmacytoid dendritic cells (pDCs) expressing IL-23 receptors constitutively produced Ifna, which plays a role in single positive (SP) cell maturation, in an Il23a-dependent manner. Neutrophil depletion with anti-Ly6G antibody injection resulted in a significant decrease of Ifna expression in the thymic pDCs, suggesting that thymic neutrophil activation underlies the Ifna expression in thymic pDCs in steady state conditions. A New Zealand White mouse strain showing HC hyperplasia exhibited greater numbers and activation of thymic neutrophils and pDCs than B6 mice, whereas Aire-deficient B6 mice with defective HC development and SP thymocyte maturation showed significantly compromised numbers and activation of these cells. These results collectively suggested that HC-mTECs with cell-senescence features initiate a unique cell activation cascade including neutrophils and pDCs leading to the constitutive IFNα expression required for SP T-cell maturation in the thymic medulla.


Assuntos
Senescência Celular , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interferon-alfa/biossíntese , Neutrófilos/imunologia , Neutrófilos/metabolismo , Timo/imunologia , Animais , Células Cultivadas , Células Dendríticas/citologia , Humanos , Interferon-alfa/metabolismo , Camundongos , Camundongos Endogâmicos , Neutrófilos/citologia , Timo/citologia
10.
Immunol Rev ; 271(1): 38-55, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27088906

RESUMO

The thymus consists of two distinct anatomical regions, the cortex and the medulla; medullary thymic epithelial cells (mTECs) play a crucial role in establishing central T-cell tolerance for self-antigens. Although the understanding of mTEC development in thymic organogenesis as well as the regulation of their differentiation and maturation has improved, the mechanisms of postnatal maintenance remain poorly understood. This issue has a central importance in immune homeostasis and physiological thymic involution as well as autoimmune disorders in various clinicopathological settings. Recently, several reports have demonstrated the existence of TEC stem or progenitor cells in the postnatal thymus, which are either bipotent or unipotent. We identified stem cells specified for mTEC-lineage that are generated in the thymic ontogeny and may sustain mTEC regeneration and lifelong central T-cell self-tolerance. This finding suggested that the thymic medulla is maintained autonomously by its own stem cells. Although several issues, including the relationship with other putative TEC stem/progenitors, remain unclear, further examination of mTEC stem cells (mTECSCs) and their regulatory mechanisms may contribute to the understanding of postnatal immune homeostasis. Possible relationships between decline of mTECSC activity and early thymic involution as well as various autoimmune disorders are discussed.


Assuntos
Doenças Autoimunes/imunologia , Autorrenovação Celular , Células Epiteliais/fisiologia , Células-Tronco/fisiologia , Linfócitos T/fisiologia , Timo/fisiologia , Animais , Diferenciação Celular , Humanos , Tolerância a Antígenos Próprios , Nicho de Células-Tronco , Timo/anatomia & histologia
11.
Cancer Sci ; 110(4): 1317-1330, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30767320

RESUMO

Adult long-term hematopoiesis depends on sustaining hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) niches, where their balance of quiescence, self-renewal, and hematopoietic differentiation is tightly regulated. Although various BM stroma cells that produce niche factors have been identified, regulation of the intrinsic responsiveness of HSPC to the niche factors remains elusive. We previously reported that mice deficient for Sipa1, a Rap1 GTPase-activating protein, develop diverse hematopoietic disorders of late onset. Here we showed that transplantation of BM cells expressing membrane-targeted C3G (C3G-F), a Rap1 GTP/GDP exchanger, resulted in the progressive decline of the numbers of HSPC repopulated in BM with time and impaired long-term hematopoiesis of all cell lineages. C3G-F/HSPC were sustained for months in spleen retaining hematopoietic potential, but these cells inefficiently contributed to overall hematopoietic reconstitution. C3G-F/HSPC showed enhanced proliferation and differentiation with accelerated progenitor cell exhaustion in response to stem cell factor (SCF). Using a Ba/F3 cell line, we confirmed that the increased basal Rap1GTP levels with C3G-F expression caused a markedly prolonged activation of c-Kit receptor and downstream signaling through SCF ligation. A minor population of C3G-F/HSPC also showed enhanced proliferation in the presence of thrombopoietin (TPO) compared to Vect/HSPC. Current results suggest an important role of basal Rap1 activation status of HSPC in their maintenance in BM for sustaining long-term adult hematopoiesis.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Transdução de Sinais , Proteínas de Ligação a Telômeros/metabolismo , Animais , Biomarcadores , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Imunofenotipagem , Camundongos , Proteínas Proto-Oncogênicas c-kit/metabolismo , Complexo Shelterina , Fator de Células-Tronco/farmacologia , Proteínas rap de Ligação ao GTP/metabolismo
12.
Eur J Immunol ; 48(10): 1663-1678, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30058200

RESUMO

Naïve phenotype (NP) T cells spontaneously initiate homeostatic proliferation (HP) as T-cell output is reduced because of physiologic thymic involution with age. However, the effects of sustained HP on overall immune function are poorly understood. We demonstrated that the NP CD8+ T cell population in adult thymectomized mice showing accelerated HP has an increased capacity for TCR-mediated interferon-γ and tumor necrosis factor α production, which is attributed to an increase in CXCR3+ cells in the NP CD8+ T cell population. The CXCR3+ NP CD8+ T cells developed during persistent HP with a slow cell division rate, but rarely during robust antigen-driven proliferation with a fast cell division rate. In ontogeny, the proportions of CXCR3+ cells in the NP CD8+ T cell population showed a biphasic profile, which was high at the newborn and aged stages. Upon transfer, CXCR3+ NP CD8+ T cells, but not CXCR3- NP CD8+ T cells, potently enhanced Th17-mediated inflammatory tissue reactions in vivo. Furthermore, CXCR3high NP CD8+ T cells with similar features were also detected at variable levels in healthy human blood. These results suggest that CXCR3+ NP CD8+ T cells generated during physiological HP significantly impact overall immunity at the immunologically vulnerable neonatal and aged stages.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Interferon gama/biossíntese , Receptores CXCR3/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Divisão Celular , Células Cultivadas , Citometria de Fluxo , Homeostase , Humanos , Interferon gama/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Células Th17/imunologia
13.
J Immunol ; 199(1): 138-148, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28539430

RESUMO

Immune aging may underlie various aging-related disorders, including diminished resistance to infection, chronic inflammatory disorders, and autoimmunity. PD-1+ and CD153+ CD44high CD4+ T cells with features of cellular senescence, termed senescence-associated T (SA-T) cells, increasingly accumulate with age and may play a role in the immune aging phenotype. In this article, we demonstrate that, compared with young mice, the aged mouse environment is highly permissive for spontaneous proliferation of transferred naive CD4+ T cells, and it drives their transition to PD-1+ and CD153+ CD44high CD4+ T cells after extensive cell divisions. CD4+ T cells with essentially the same features as SA-T cells in aged mice are also generated from naive CD4+ T cells after extensive cell divisions under severe T-lymphopenic conditions by gamma irradiation or in developmental T cell defect, often in association with spontaneous germinal centers, as seen in aged mice. The increase in SA-T cells is significantly enhanced after thymectomy at the young adult stage, along with accelerated T cell homeostatic proliferation, whereas embryonic thymus implantation in the late adult stage markedly restricts the homeostatic proliferation of naive CD4+ T cells in the host and delays the increase in SA-T cells. Our results suggest that reduced T cell output due to physiologic thymic involution underlies the age-dependent accumulation of SA-T cells as a result of increasing homeostatic proliferation of naive CD4+ T cells. SA-T cells may provide a suitable biomarker of immune aging, as well as a potential target for controlling aging-related disorders.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Senescência Celular , Timo/imunologia , Timo/fisiologia , Animais , Autoimunidade , Biomarcadores , Ligante CD30/imunologia , Diferenciação Celular , Centro Germinativo/imunologia , Receptores de Hialuronatos/imunologia , Ativação Linfocitária , Camundongos , Fenótipo , Receptor de Morte Celular Programada 1/imunologia , Timo/citologia
14.
Cancer Sci ; 109(3): 587-599, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29288540

RESUMO

Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in a major histocombatibility complex (MHC) -unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αß T cells resulted in some mice with circulating human αß T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor-α and interferon-γ in response to PTA-treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed up the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA-matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses.


Assuntos
Neoplasias da Mama/terapia , Difosfonatos/administração & dosagem , Pró-Fármacos/administração & dosagem , Neoplasias da Próstata/terapia , Linfócitos T/transplante , Animais , Neoplasias da Mama/imunologia , Difosfonatos/química , Difosfonatos/farmacologia , Feminino , Humanos , Imunoterapia Adotiva , Masculino , Camundongos , Pró-Fármacos/farmacologia , Neoplasias da Próstata/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Immunol ; 197(6): 2177-86, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27534552

RESUMO

Disposal of apoptotic cells is important for tissue homeostasis. Defects in this process in immune tissues may lead to breakdown of self-tolerance against intracellular molecules, including nuclear components. Development of diverse anti-nuclear Abs (ANAs) is a hallmark of lupus, which may arise, in part, due to impaired apoptotic cell clearance. In this work, we demonstrate that spontaneous germinal centers (GCs) in lupus-prone mice contain significantly elevated levels of unengulfed apoptotic cells, which are otherwise swiftly engulfed by tingible body macrophages. We indicate that osteopontin (OPN) secreted by CD153(+) senescence-associated T cells, which selectively accumulate in the GCs of lupus-prone mice, interferes with phagocytosis of apoptotic cells specifically captured via MFG-E8. OPN induced diffuse and prolonged Rac1 activation in phagocytes via integrin αvß3 and inhibited the dissolution of phagocytic actin cup, causing defective apoptotic cell engulfment. In wild-type B6 mice, administration of TLR7 ligand also caused spontaneous GC reactions with increasing unengulfed apoptotic cells and ANA production, whereas B6 mice deficient for Spp1 encoding OPN showed less apoptotic cells and developed significantly reduced ANAs in response to TLR7 ligand. Our results suggest that OPN secreted by follicular CD153(+) senescence-associated T cells in GCs promotes a continuous supply of intracellular autoantigens via apoptotic cells, thus playing a key role in the progression of the autoreactive GC reaction and leading to pathogenic autoantibody production in lupus-prone mice.


Assuntos
Anticorpos Antinucleares/biossíntese , Apoptose , Centro Germinativo/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Osteopontina/fisiologia , Animais , Ligante CD30/análise , Células Cultivadas , Integrina alfaVbeta3/fisiologia , Lúpus Eritematoso Sistêmico/patologia , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/fisiologia , Fagocitose , Receptor 7 Toll-Like/fisiologia , Proteínas rac1 de Ligação ao GTP/fisiologia
16.
Cell Struct Funct ; 42(2): 149-157, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29070774

RESUMO

Bone marrow stromal cells, including endothelial cells and mesenchymal stromal cells, support the maintenance, differentiation, and retention of hematopoietic stem and precursor cells under steady state conditions. At the onset of an emergency, such as severe blood loss or infection, the status of hematopoiesis in the bone marrow changes rapidly to ensure efficient production of cells of specific lineages; however, the function of stromal cells in emergency hematopoiesis has not been fully elucidated. Here, we unexpectedly found that B precursor, mature B, and T cells were released from the bone marrow into the blood circulation in the early phase of hemorrhagic anemia and phenylhydrazine-induced hemolytic anemia. Administration of erythropoietin, which normally increases in response to anemia, stimulated the egress of IgDlow immature B cells and recirculating mature B cells, which usually reside in the perivascular and intravascular space, from the bone marrow within 24 h. We also observed that endothelial cells in the bone marrow expressed erythropoietin receptor, and the expression levels were higher than those in other tissues. Erythropoietin stimulation of bone marrow endothelial cells induced the phosphorylation of STAT5 in vitro. Moreover, in vivo treatment with erythropoietin decreased surface VCAM1 expression and Cxcl12 transcription in bone marrow endothelial cells, both of which are essential for immature and mature B cell retention in the bone marrow. These results suggest that bone marrow endothelial cells can sense and rapidly respond to erythropoietin increase during anemia, thereby regulating B cell emigration from the bone marrow during emergency hematopoiesis.Key words: erythropoietin, anemia, endothelial cells, B cell, bone marrow microenvironment.


Assuntos
Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Eritropoetina/farmacologia , Animais , Linfócitos B/metabolismo , Células da Medula Óssea/metabolismo , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Células Endoteliais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
17.
J Cell Sci ; 128(12): 2302-13, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25967549

RESUMO

G-protein-coupled receptors (GPCRs) are key players in cell signaling, and their cell surface expression is tightly regulated. For many GPCRs such as ß2-AR (ß2-adrenergic receptor), receptor activation leads to downregulation of receptor surface expression, a phenomenon that has been extensively characterized. By contrast, some other GPCRs, such as GABA(B) receptor, remain relatively stable at the cell surface even after prolonged agonist treatment; however, the underlying mechanisms are unclear. Here, we identify the small GTPase Rap1 as a key regulator for promoting GABA(B) receptor surface expression. Agonist stimulation of GABA(B) receptor signals through Gαi/o to inhibit Rap1GAPII (also known as Rap1GAP1b, an isoform of Rap1GAP1), thereby activating Rap1 (which has two isoforms, Rap1a and Rap1b) in cultured cerebellar granule neurons (CGNs). The active form of Rap1 is then recruited to GABA(B) receptor through physical interactions in CGNs. This Rap1-dependent signaling cascade promotes GABA(B) receptor surface expression by stimulating receptor recycling. Our results uncover a new mechanism regulating GPCR surface expression and also provide a potential explanation for the slow, long-lasting inhibitory action of GABA neurotransmitter.


Assuntos
Membrana Celular/metabolismo , Endocitose/fisiologia , Neurônios/metabolismo , Receptores de GABA-B/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo , Sequência de Aminoácidos , Animais , Biotinilação , Western Blotting , Células Cultivadas , Feminino , Citometria de Fluxo , Imunofluorescência , Masculino , Camundongos , Dados de Sequência Molecular , Neurônios/citologia , Fosforilação , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
18.
J Immunol ; 194(12): 5725-35, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25972477

RESUMO

Immune aging results in diminished adaptive immunity and increased risk for autoimmunity. We previously reported a unique PD-1(+) CD44(high)CD4(+) T cell population that increases with age in normal mice. In this study, we indicate that the age-dependent PD-1(+) CD44(high)CD4(+) T cells develop as unique T follicular (TF) cells in a B cell-dependent manner and consist of two subpopulations, as follows: CD153(+) cells preferentially secreting abundant osteopontin on TCR stimulation and CD153(-) cells that are apparently TCR anergic. These unique TF cells with essentially similar features increase much earlier and are accumulated in the spontaneous germinal centers (GCs) in lupus-prone female BWF1 (f-BWF1) mice. These TF cells showed characteristic cell-senescence features and developed in association with extensive CD4(+) T cell proliferation in vivo, suggesting replicative senescence. Although the CD153(+) TF cells were defective in proliferation capacity, they were quite stable and specifically responded to self GC-B cells to secret abundant osteopontin, which inhibited B cell receptor-induced GC-B cell apoptosis in f-BWF1 mice. Transfer of CD153(+) PD-1(+) CD4(+) T cells promoted the growth of spontaneous GCs, whereas administration of anti-osteopontin Ab suppressed GC enlargement and anti-nuclear Ab production and ameliorated clinical lupus nephritis of f-BWF1 mice. Current results suggest that senescent CD153(+) TF cells generated as a consequence of extensive endogenous CD4(+) T cell proliferation play an essential, if not sufficient, role in lupus pathogenesis in lupus-prone genetic background and may also contribute to an increased autoimmunity risk with age.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Senescência Celular/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Osteopontina/biossíntese , Animais , Apoptose , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ligante CD30/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Feminino , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Imunofenotipagem , Nefrite Lúpica/patologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
19.
J Transl Med ; 14(1): 295, 2016 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-27756323

RESUMO

The goal of biomarker research is to identify clinically valid markers. Despite decades of research there has been disappointingly few molecules or techniques that are in use today. The "1st International NTNU Symposium on Current and Future Clinical Biomarkers of Cancer: Innovation and Implementation", was held June 16th and 17th 2016, at the Knowledge Center of the St. Olavs Hospital in Trondheim, Norway, under the auspices of the Norwegian University of Science and Technology (NTNU) and the HUNT biobank and research center. The Symposium attracted approximately 100 attendees and invited speakers from 12 countries and 4 continents. In this Symposium original research and overviews on diagnostic, predictive and prognostic cancer biomarkers in serum, plasma, urine, pleural fluid and tumor, circulating tumor cells and bioinformatics as well as how to implement biomarkers in clinical trials were presented. Senior researchers and young investigators presented, reviewed and vividly discussed important new developments in the field of clinical biomarkers of cancer, with the goal of accelerating biomarker research and implementation. The excerpts of this symposium aim to give a cutting-edge overview and insight on some highly important aspects of clinical cancer biomarkers to-date to connect molecular innovation with clinical implementation to eventually improve patient care.


Assuntos
Biomarcadores Tumorais/metabolismo , Internacionalidade , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/urina , Bases de Dados como Assunto , Humanos , Neoplasias/sangue , Neoplasias/patologia , Neoplasias/urina , Noruega , Reprodutibilidade dos Testes
20.
Nat Genet ; 39(4): 467-75, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17369830

RESUMO

Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using cis-Apc(+/Delta716) Smad4(+/-) mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-beta family signaling is blocked, we show here that a new type of immature myeloid cell (iMC) is recruited from the bone marrow to the tumor invasion front. These CD34(+) iMCs express the matrix metalloproteinases MMP9 and MMP2 and the CC-chemokine receptor 1 (CCR1) and migrate toward the CCR1 ligand CCL9. In adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the cis-Apc/Smad4 mutant, we further show that lack of CCR1 prevents accumulation of CD34(+) iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of transforming growth factor-beta family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.


Assuntos
Carcinoma/genética , Movimento Celular/genética , Neoplasias Intestinais/genética , Células Mieloides/metabolismo , Receptores de Quimiocinas/metabolismo , Proteína Smad4/genética , Animais , Antígenos CD34/metabolismo , Carcinoma/patologia , Quimiocinas CC , Feminino , Neoplasias Intestinais/patologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Invasividade Neoplásica/genética , Receptores CCR1 , Receptores de Quimiocinas/genética , Células Estromais/metabolismo , Células Tumorais Cultivadas
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