RESUMO
To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8+ tumor-infiltrating lymphocytes away from exhausted effector states remains an elusive goal. Our work provides evidence that orthogonal gene engineering of T cells to secrete an interleukin (IL)-2 variant binding the IL-2Rßγ receptor and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic effector state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host and led-in the absence of lymphodepletion or exogenous cytokine support-to high levels of engraftment and tumor regression. Our work unlocks a new opportunity of rationally engineering synthetic CD8+ T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.
Assuntos
Linfócitos T CD8-Positivos , Imunoterapia Adotiva , Interleucina-2 , Neoplasias Experimentais , Linfócitos T CD8-Positivos/imunologia , Exaustão das Células T , Linfócitos do Interstício Tumoral/imunologia , Interleucina-2/farmacologia , Interleucina-33 , Engenharia de Proteínas , Feminino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Neoplasias Experimentais/terapia , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Lymph nodes (LNs) comprise two main structural elements: fibroblastic reticular cells that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. Immunological challenge causes LNs to increase more than tenfold in size within a few days. Here, we characterized the biomechanics of LN swelling on the cellular and organ scale. We identified lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing fibroblastic reticular cells of the T-zone (TRCs) and their associated conduits to stretch. After an initial phase of relaxation, TRCs sensed the resulting strain through cell matrix adhesions, which coordinated local growth and remodeling of the stromal network. While the expanded TRC network readopted its typical configuration, a massive fibrotic reaction of the organ capsule set in and countered further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multitier fashion.
Assuntos
Linfonodos , Células Estromais , Animais , Fibroblastos , Linfócitos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
T cell factor 1 (Tcf-1) expressing CD8+ T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8+ T cells (CD8+SL) remain poorly defined. Studying CD8+ T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8+SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8+ T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8+SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8+SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8+SL and determined these cells' re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8+SL-promoting pathway in the context of chronic viral infection.
Assuntos
Linfócitos T CD8-Positivos , Interleucina-33 , Coriomeningite Linfocítica , Animais , Camundongos , Alarminas/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica , Camundongos Endogâmicos C57BL , Infecção Persistente , Fator 1 de Transcrição de Linfócitos T/metabolismoRESUMO
Central memory CD8+ T cells (Tcm) control systemic secondary infections and can protect from chronic infection and cancer as a result of their stem-cell-like capacity to expand, differentiate, and self-renew. Central memory is generally thought to emerge following pathogen clearance and to form based on the de-differentiation of cytolytic effector cells. Here, we uncovered rare effector-phase CD8+ T cells expressing high amounts of the transcription factor Tcf7 (Tcf1) that showed no evidence of prior cytolytic differentiation and that displayed key hallmarks of Tcm cells. These effector-phase Tcf7hi cells quantitatively yielded Tcm cells based on lineage tracing. Mechanistically, Tcf1 counteracted the differentiation of Tcf7hi cells and sustained the expression of conserved adult stem-cell genes that were critical for CD8+ T cell stemness. The discovery of stem-cell-like CD8+ T cells during the effector response to acute infection provides an opportunity to optimize Tcm cell formation by vaccination.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Citotoxicidade Imunológica , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Memória Imunológica , Fator 1 de Transcrição de Linfócitos T/metabolismo , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/genética , Montagem e Desmontagem da Cromatina , Citotoxicidade Imunológica/genética , Imunofluorescência , Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/química , Fator 1-alfa Nuclear de Hepatócito/genética , Humanos , Imunização , Memória Imunológica/genética , Imunofenotipagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Conformação Proteica , Baço/imunologia , Baço/metabolismo , Relação Estrutura-Atividade , Fator 1 de Transcrição de Linfócitos T/química , Fator 1 de Transcrição de Linfócitos T/genéticaRESUMO
Regions of the normal arterial intima predisposed to atherosclerosis are sites of ongoing monocyte trafficking and also contain resident myeloid cells with features of dendritic cells. However, the pathophysiological roles of these cells are poorly understood. Here we found that intimal myeloid cells underwent reverse transendothelial migration (RTM) into the arterial circulation after systemic stimulation of pattern-recognition receptors (PRRs). This process was dependent on expression of the chemokine receptor CCR7 and its ligand CCL19 by intimal myeloid cells. In mice infected with the intracellular pathogen Chlamydia muridarum, blood monocytes disseminated infection to the intima. Subsequent CCL19-CCR7-dependent RTM was critical for the clearance of intimal C. muridarum. This process was inhibited by hypercholesterolemia. Thus, RTM protects the normal arterial intima, and compromised RTM during atherogenesis might contribute to the intracellular retention of pathogens in atherosclerotic lesions.
Assuntos
Quimiocina CCL19/metabolismo , Chlamydia muridarum/imunologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores CCR7/metabolismo , Migração Transendotelial e Transepitelial , Túnica Íntima/imunologia , Túnica Íntima/metabolismo , Animais , Antígeno CD11c/metabolismo , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/metabolismo , Infecções por Chlamydia/virologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/microbiologia , RNA Mensageiro/genética , Transdução de Sinais , Receptores Toll-Like/metabolismo , Túnica Íntima/microbiologiaRESUMO
Checkpoint blockade mediates a proliferative response of tumor-infiltrating CD8+ T lymphocytes (TILs). The origin of this response has remained elusive because chronic activation promotes terminal differentiation or exhaustion of tumor-specific T cells. Here we identified a subset of tumor-reactive TILs bearing hallmarks of exhausted cells and central memory cells, including expression of the checkpoint protein PD-1 and the transcription factor Tcf1. Tcf1+PD-1+ TILs mediated the proliferative response to immunotherapy, generating both Tcf1+PD-1+ and differentiated Tcf1-PD-1+ cells. Ablation of Tcf1+PD-1+ TILs restricted responses to immunotherapy. Tcf1 was not required for the generation of Tcf1+PD-1+ TILs but was essential for the stem-like functions of these cells. Human TCF1+PD-1+ cells were detected among tumor-reactive CD8+ T cells in the blood of melanoma patients and among TILs of primary melanomas. Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Células-Tronco/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diferenciação Celular , Proliferação de Células , Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores , Fator 1-alfa Nuclear de Hepatócito/genética , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Melanoma/imunologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Stromal cells (SCs) establish the compartmentalization of lymphoid tissues critical to the immune response. However, the full diversity of lymph node (LN) SCs remains undefined. Using droplet-based single-cell RNA sequencing, we identified nine peripheral LN non-endothelial SC clusters. Included are the established subsets, Ccl19hi T-zone reticular cells (TRCs), marginal reticular cells, follicular dendritic cells (FDCs), and perivascular cells. We also identified Ccl19lo TRCs, likely including cholesterol-25-hydroxylase+ cells located at the T-zone perimeter, Cxcl9+ TRCs in the T-zone and interfollicular region, CD34+ SCs in the capsule and medullary vessel adventitia, indolethylamine N-methyltransferase+ SCs in the medullary cords, and Nr4a1+ SCs in several niches. These data help define how transcriptionally distinct LN SCs support niche-restricted immune functions and provide evidence that many SCs are in an activated state.
Assuntos
Linfonodos/imunologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Células Estromais/imunologia , Transcriptoma/imunologia , Animais , Quimiocina CCL19/genética , Quimiocina CCL19/imunologia , Quimiocina CCL19/metabolismo , Células Dendríticas Foliculares/imunologia , Células Dendríticas Foliculares/metabolismo , Feminino , Linfonodos/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos Endogâmicos C57BL , Células Estromais/metabolismoRESUMO
Antibody-producing plasma cells fuel humoral immune responses. They also contribute to autoimmune diseases such as systemic lupus erythematosus or IgA nephropathy. Interleukin-6 and the tumor necrosis factor (TNF) family ligands BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) participate in plasma cell survival. BAFF binds to three receptors, BAFFR (BAFF receptor), TACI (transmembrane activator and CAML interactor), and BCMA (B cell maturation antigen), while APRIL binds to TACI, BCMA, and proteoglycans. However, which ligand-receptor pair(s) are required to maintain plasma cells in different body locations remains unknown. Here, by combining mouse genetic and pharmacological approaches, we found that plasma cells required BCMA and/or TACI but not BAFFR. BCMA responded exclusively to APRIL, while TACI responded to both BAFF and APRIL, identifying three self-sufficient ligand-receptor pairs for plasma cell maintenance: BAFF-TACI, APRIL-TACI, and APRIL-BCMA. Together, these actors accounted for 90% of circulating antibodies. In BAFF-ko mice, the reduction of plasma cells upon APRIL inhibition indicated that APRIL could function in the absence of BAFF-APRIL heteromers. No evidence was found that in the absence of BCMA and TACI, binding of APRIL to proteoglycans would help maintain plasma cells. IL-6, alone or together with BAFF and APRIL, supported mainly splenic plasmablasts and plasma cells and contributed to circulating IgG but not IgA levels. In conclusion, survival factors for plasma cells can vary with body location and with the antibody isotype that plasma cells produce. To efficiently target plasma cells, in particular IgA-producing ones, dual inhibition of BAFF and APRIL is required.
Assuntos
Fator Ativador de Células B , Receptor do Fator Ativador de Células B , Antígeno de Maturação de Linfócitos B , Interleucina-6 , Proteína Transmembrana Ativadora e Interagente do CAML , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Animais , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Fator Ativador de Células B/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Antígeno de Maturação de Linfócitos B/imunologia , Antígeno de Maturação de Linfócitos B/metabolismo , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Proteína Transmembrana Ativadora e Interagente do CAML/imunologia , Interleucina-6/metabolismo , Interleucina-6/imunologia , Camundongos , Receptor do Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/genética , Plasmócitos/imunologia , Plasmócitos/metabolismo , Camundongos Knockout , Células Produtoras de Anticorpos/imunologia , Células Produtoras de Anticorpos/metabolismo , Camundongos Endogâmicos C57BLRESUMO
The protease MALT1 promotes lymphocyte activation and lymphomagenesis by cleaving a limited set of cellular substrates, most of which control gene expression. Here, we identified the integrin-binding scaffold protein Tensin-3 as a MALT1 substrate in activated human B cells. Activated B cells lacking Tensin-3 showed decreased integrin-dependent adhesion but exhibited comparable NF-κB1 and Jun N-terminal kinase transcriptional responses. Cells expressing a noncleavable form of Tensin-3, on the other hand, showed increased adhesion. To test the role of Tensin-3 cleavage in vivo, mice expressing a noncleavable version of Tensin-3 were generated, which showed a partial reduction in the T cell-dependent B cell response. Interestingly, human diffuse large B cell lymphomas and mantle cell lymphomas with constitutive MALT1 activity showed strong constitutive Tensin-3 cleavage and a decrease in uncleaved Tensin-3 levels. Moreover, silencing of Tensin-3 expression in MALT1-driven lymphoma promoted dissemination of xenografted lymphoma cells to the bone marrow and spleen. Thus, MALT1-dependent Tensin-3 cleavage reveals a unique aspect of the function of MALT1, which negatively regulates integrin-dependent B cell adhesion and facilitates metastatic spread of B cell lymphomas.
Assuntos
Caspases , Linfoma Difuso de Grandes Células B , Camundongos , Humanos , Animais , Adulto , Tensinas/genética , Caspases/metabolismo , NF-kappa B/metabolismo , Adesão Celular/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Linfoma Difuso de Grandes Células B/genética , IntegrinasRESUMO
Upon viral infection, stressed or damaged cells can release alarmins like IL-33 that act as endogenous danger signals alerting innate and adaptive immune cells. IL-33 coming from nonhematopoietic cells has been identified as important factor triggering the expansion of antiviral CD8+ T cells. In LN the critical cellular source of IL-33 is unknown, as is its potential cell-intrinsic function as a chromatin-associated factor. Using IL-33-GFP reporter mice, we identify fibroblastic reticular cells (FRC) and lymphatic endothelial cells (LEC) as the main IL-33 source. In homeostasis, IL-33 is dispensable as a transcriptional regulator in FRC, indicating it functions mainly as released cytokine. Early during infection with lymphocytic choriomeningitis virus (LCMV) clone 13, both FRC and LEC lose IL-33 protein expression suggesting cytokine release, correlating timewise with IL-33 receptor expression by reactive CD8+ T cells and their greatly augmented expansion in WT versus ll33-/- mice. Using mice lacking IL-33 selectively in FRC versus LEC, we identify FRC as key IL-33 source driving acute and chronic antiviral T-cell responses. Collectively, these findings show that LN T-zone FRC not only regulate the homeostasis of naïve T cells but also their expansion and differentiation several days into an antiviral response.
Assuntos
Interleucina-33/metabolismo , Coriomeningite Linfocítica/imunologia , Doença Aguda , Imunidade Adaptativa , Animais , Linfócitos T CD8-Positivos/imunologia , Doença Crônica , Células Endoteliais/imunologia , Fibroblastos/imunologia , Homeostase , Humanos , Imunidade Inata , Interleucina-33/deficiência , Interleucina-33/genética , Linfonodos/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos ImunológicosRESUMO
The stromal scaffold of the lymph node (LN) paracortex is built by fibroblastic reticular cells (FRCs). Conditional ablation of lymphotoxin-ß receptor (LTßR) expression in LN FRCs and their mesenchymal progenitors in developing LNs revealed that LTßR-signaling in these cells was not essential for the formation of LNs. Although T cell zone reticular cells had lost podoplanin expression, they still formed a functional conduit system and showed enhanced expression of myofibroblastic markers. However, essential immune functions of FRCs, including homeostatic chemokine and interleukin-7 expression, were impaired. These changes in T cell zone reticular cell function were associated with increased susceptibility to viral infection. Thus, myofibroblasic FRC precursors are able to generate the basic T cell zone infrastructure, whereas LTßR-dependent maturation of FRCs guarantees full immunocompetence and hence optimal LN function during infection.
Assuntos
Infecções por Coronavirus/imunologia , Linfonodos/citologia , Linfonodos/metabolismo , Miofibroblastos/fisiologia , Linfócitos T/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/imunologia , Interleucina-7/biossíntese , Linfonodos/imunologia , Receptor beta de Linfotoxina/metabolismo , Linfotoxina-beta/biossíntese , Linfotoxina-beta/metabolismo , Glicoproteínas de Membrana/biossíntese , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vírus da Hepatite Murina/imunologia , Miofibroblastos/citologia , Transdução de SinaisRESUMO
Lymphoid T-zone fibroblastic reticular cells (FRCs) actively promote T-cell trafficking, homeostasis, and expansion but can also attenuate excessive T-cell responses via inducible nitric oxide (NO) and constitutive prostanoid release. It remains unclear how these FRC-derived mediators dampen T-cell responses and whether this occurs in vivo. Here, we confirm that murine lymph node (LN) FRCs produce prostaglandin E2 (PGE2) in a cyclooxygenase-2 (COX2)-dependent and inflammation-independent fashion. We show that this COX2/PGE2 pathway is active during both strong and weak T-cell responses, in contrast to NO, which only comes into play during strong T-cell responses. During chronic infections in vivo, PGE2-receptor signaling in virus-specific cluster of differentiation (CD)8 cytotoxic T cells was shown by others to suppress T-cell survival and function. Using COX2flox/flox mice crossed to mice expressing Cre recombinase expression under control of the CC chemokine ligand (CCL19) promoter (CCL19cre), we now identify CCL19+ FRC as the critical source of this COX2-dependent suppressive factor, suggesting PGE2-expressing FRCs within lymphoid tissues are an interesting therapeutic target to improve T-cell-mediated pathogen control during chronic infection.
Assuntos
Ciclo-Oxigenase 2/imunologia , Fibroblastos/imunologia , Linfonodos/imunologia , Prostaglandinas/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular , Movimento Celular/genética , Movimento Celular/imunologia , Proliferação de Células/genética , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Fibroblastos/metabolismo , Fibroblastos/virologia , Linfonodos/citologia , Linfonodos/metabolismo , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Prostaglandinas/biossíntese , Linfócitos T/virologiaRESUMO
Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.
Assuntos
Fibroblastos/patologia , Estruturas Linfoides Terciárias/patologia , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Imunofluorescência , Humanos , Interleucina-13/metabolismo , Interleucinas/metabolismo , Linfócitos/patologia , Camundongos , Glândulas Salivares/patologia , Interleucina 22RESUMO
Antibody-secreting plasma cells (PCs) arise rapidly during adaptive immunity to control infections. The early PCs are retained within the reactive lymphoid organ where their localization and homeostasis rely on extrinsic factors, presumably produced by local niche cells. While myeloid cells have been proposed to form those niches, the contribution by colocalizing stromal cells has remained unclear. Here, we characterized a subset of fibroblastic reticular cells (FRCs) that forms a dense meshwork throughout medullary cords of lymph nodes (LNs) where PCs reside. This medullary FRC type is shown to be anatomically, phenotypically, and functionally distinct from T zone FRCs, both in mice and humans. By using static and dynamic imaging approaches, we provide evidence that medullary FRCs are the main cell type in contact with PCs guiding them in their migration. Medullary FRCs also represent a major local source of the PC survival factors IL-6, BAFF, and CXCL12, besides also producing APRIL. In vitro, medullary FRCs alone or in combination with macrophages promote PC survival while other LN cell types do not have this property. Thus, we propose that this FRC subset, together with medullary macrophages, forms PC survival niches within the LN medulla, and thereby helps in promoting the rapid development of humoral immunity, which is critical in limiting early pathogen spread.
Assuntos
Formação de Anticorpos , Homeostase/imunologia , Linfonodos/imunologia , Plasmócitos/imunologia , Animais , Fator Ativador de Células B/imunologia , Quimiocina CXCL12/imunologia , Interleucina-6/imunologia , Linfonodos/citologia , Masculino , Camundongos , Plasmócitos/citologia , Células Estromais/citologia , Células Estromais/imunologiaRESUMO
The generation of lymphoid microenvironments in early life depends on the interaction of lymphoid tissue-inducer cells with stromal lymphoid tissue-organizer cells. Whether this cellular interface stays operational in adult secondary lymphoid organs has remained elusive. We show here that during acute infection with lymphocytic choriomeningitis virus, antiviral cytotoxic T cells destroyed infected T cell zone stromal cells, which led to profound disruption of secondary lymphoid organ integrity. Furthermore, the ability of the host to respond to secondary antigens was lost. Restoration of the lymphoid microanatomy was dependent on the proliferative accumulation of lymphoid tissue-inducer cells in secondary lymphoid organs during the acute phase of infection and lymphotoxin alpha(1)beta(2) signaling. Thus, crosstalk between lymphoid tissue-inducer cells and stromal cells is reactivated in adults to maintain secondary lymphoid organ integrity and thereby contributes to the preservation of immunocompetence.
Assuntos
Infecções por Arenaviridae/imunologia , Sistema Linfático/fisiologia , Vírus da Coriomeningite Linfocítica/imunologia , Células Estromais/metabolismo , Linfócitos T Citotóxicos/imunologia , Animais , Infecções por Arenaviridae/sangue , Infecções por Arenaviridae/virologia , Ativação Linfocitária/imunologia , Tecido Linfoide/imunologia , Especificidade de Órgãos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Auxiliares-IndutoresRESUMO
During αß T cell development in the thymus, migration of newly selected CD4+ and CD8+ thymocytes into medullary areas enables tolerance mechanisms to purge the newly selected αß TCR repertoire of autoreactive specificities. Thymic dendritic cells (DC) play key roles in this process and consist of three distinct subsets that differ in their developmental origins. Thus, plasmacytoid DC and Sirpα+ conventional DC type 2 are extrathymically derived and enter into the thymus via their respective expression of the chemokine receptors CCR9 and CCR2. In contrast, although Sirpα- conventional DC type 1 (cDC1) are known to arise intrathymically from immature progenitors, the precise nature of such thymus-colonizing progenitors and the mechanisms controlling their thymus entry are unclear. In this article, we report a selective reduction in thymic cDC1 in mice lacking the chemokine receptor CCR7. In addition, we show that the thymus contains a CD11c+MHC class II-Sirpα-Flt3+ cDC progenitor population that expresses CCR7, and that migration of these cells to the thymus is impaired in Ccr7-/- mice. Moreover, thymic cDC1 defects in Ccr7-/- mice are mirrored in plt/plt mice, with further analysis of mice individually lacking the CCR7 ligands CCL21Ser (Ccl21a-/- ) or CCL19 (Ccl19-/-) demonstrating an essential role for CCR7-CCL21Ser during intrathymic cDC1 development. Collectively, our data support a mechanism in which CCR7-CCL21Ser interactions guide the migration of cDC progenitors to the thymus for correct formation of the intrathymic cDC1 pool.
Assuntos
Quimiocina CCL21/metabolismo , Células Dendríticas/metabolismo , Receptores CCR7/metabolismo , Timócitos/metabolismo , Timo/metabolismo , Animais , Movimento Celular/fisiologia , Tolerância Imunológica/fisiologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Little is known about the migration of plasma cell precursors to the lymph node medulla. In this issue of Immunity, Fooksman et al. (2010) propose that this migration is largely independent of chemotactic cues but follows a long linear walk of random orientation.
RESUMO
The protease activity of the paracaspase Malt1 has recently gained interest as a drug target for immunomodulation and the treatment of diffuse large B-cell lymphomas. To address the consequences of Malt1 protease inactivation on the immune response in vivo, we generated knock-in mice expressing a catalytically inactive C472A mutant of Malt1 that conserves its scaffold function. Like Malt1-deficient mice, knock-in mice had strong defects in the activation of lymphocytes, NK and dendritic cells, and the development of B1 and marginal zone B cells and were completely protected against the induction of autoimmune encephalomyelitis. Malt1 inactivation also protected the mice from experimental induction of colitis. However, Malt1 knock-in mice but not Malt1-deficient mice spontaneously developed signs of autoimmune gastritis that correlated with an absence of Treg cells, an accumulation of T cells with an activated phenotype and high serum levels of IgE and IgG1. Thus, removal of the enzymatic activity of Malt1 efficiently dampens the immune response, but favors autoimmunity through impaired Treg development, which could be relevant for therapeutic Malt1-targeting strategies.
Assuntos
Autoimunidade/genética , Caspases/metabolismo , Colite/imunologia , Proteínas de Ligação a DNA/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Proteínas de Neoplasias/metabolismo , Transferência Adotiva , Análise de Variância , Animais , Caspases/genética , Colite/patologia , Primers do DNA/genética , Proteínas de Ligação a DNA/genética , Encefalomielite Autoimune Experimental/patologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Técnicas de Introdução de Genes , Inativação Gênica , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imuno-Histoquímica , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/genética , Mutação Puntual/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Although Notch signaling plays important roles in lineage commitment and differentiation of multiple cell types including conventional T cells, nothing is currently known concerning Notch function in innate-like T cells. We have found that the homeostasis of several well-characterized populations of innate-like T cells including invariant NKT cells (iNKT), CD8ααTCRαß small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells is controlled by Notch. Notch selectively regulates hepatic iNKT cell survival via tissue-restricted control of B cell lymphoma 2 and IL-7Rα expression. More generally, Notch regulation of innate-like T cell homeostasis involves both cell-intrinsic and -extrinsic mechanisms and relies upon context-dependent interactions with Notch ligand-expressing fibroblastic stromal cells. Collectively, using conditional ablation of Notch receptors on peripheral T cells or Notch ligands on putative fibroblastic stromal cells, we show that Notch signaling is indispensable for the homeostasis of three tissue-restricted populations of innate-like T cells: hepatic iNKT, CD8ααTCRαß small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells, thus supporting a generalized role for Notch in innate T cell homeostasis.