Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 56
Filtrar
1.
Nat Immunol ; 22(10): 1256-1267, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34462601

RESUMO

Innate lymphoid cells (ILCs) participate in tissue homeostasis, inflammation, and early immunity against infection. It is unclear how ILCs acquire effector function and whether these mechanisms differ between organs. Through multiplexed single-cell mRNA sequencing, we identified cKit+CD127hiTCF-1hi early differentiation stages of T-bet+ ILC1s. These cells were present across different organs and had the potential to mature toward CD127intTCF-1int and CD127-TCF-1- ILC1s. Paralleling a gradual loss of TCF-1, differentiating ILC1s forfeited their expansion potential while increasing expression of effector molecules, reminiscent of T cell differentiation in secondary lymphoid organs. The transcription factor Hobit was induced in TCF-1hi ILC1s and was required for their effector differentiation. These findings reveal sequential mechanisms of ILC1 lineage commitment and effector differentiation that are conserved across tissues. Our analyses suggest that ILC1s emerge as TCF-1hi cells in the periphery and acquire a spectrum of organ-specific effector phenotypes through a uniform Hobit-dependent differentiation pathway driven by local cues.


Assuntos
Diferenciação Celular/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Fatores de Transcrição/imunologia , Animais , Feminino , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/imunologia , Linfócitos T/imunologia
2.
Nat Immunol ; 21(9): 1070-1081, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32661361

RESUMO

Tissue-resident memory CD8+ T cells (TRM cells) are crucial in protecting against reinvading pathogens, but the impact of reinfection on their tissue confinement and contribution to recall responses is unclear. We developed a unique lineage tracer mouse model exploiting the TRM-defining transcription factor homolog of Blimp-1 in T cells (Hobit) to fate map the TRM progeny in secondary responses. After reinfection, a sizeable fraction of secondary memory T cells in the circulation developed downstream of TRM cells. These tissue-experienced ex-TRM cells shared phenotypic properties with the effector memory T cell population but were transcriptionally and functionally distinct from other secondary effector memory T cell cells. Adoptive transfer experiments of TRM cells corroborated their potential to form circulating effector and memory cells during recall responses. Moreover, specific ablation of primary TRM cell populations substantially impaired the secondary T cell response, both locally and systemically. Thus, TRM cells retain developmental plasticity and shape both local and systemic T cell responses on reinfection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Transferência Adotiva , Animais , Diferenciação Celular , Linhagem da Célula , Plasticidade Celular , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética
3.
Nat Immunol ; 20(4): 514, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30846879

RESUMO

In the version of this article initially published, a portion of the Acknowledgements section ("the Clinical Research Group CEDER of the German Research Council (DFG)") was incorrect. The correct statement is as follows: "...the Collaborative Research Center TRR241 of the German Research Council (DFG)...". The error has been corrected in the HTML and PDF version of the article.

4.
Nat Immunol ; 20(3): 288-300, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692620

RESUMO

Although tissue-resident memory T cells (TRM cells) have been shown to regulate host protection in infectious disorders, their function in inflammatory bowel disease (IBD) remains to be investigated. Here we characterized TRM cells in human IBD and in experimental models of intestinal inflammation. Pro-inflammatory TRM cells accumulated in the mucosa of patients with IBD, and the presence of CD4+CD69+CD103+ TRM cells was predictive of the development of flares. In vivo, functional impairment of TRM cells in mice with double knockout of the TRM-cell-associated transcription factors Hobit and Blimp-1 attenuated disease in several models of colitis, due to impaired cross-talk between the adaptive and innate immune system. Finally, depletion of TRM cells led to a suppression of colitis activity. Together, our data demonstrate a central role for TRM cells in the pathogenesis of chronic intestinal inflammation and suggest that these cells could be targets for future therapeutic approaches in IBD.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Colite/imunologia , Memória Imunológica/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Fatores de Transcrição/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Doença Crônica , Colite/genética , Colite/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Memória Imunológica/genética , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fator 1 de Ligação ao Domínio I Regulador Positivo/deficiência , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
5.
Nat Immunol ; 19(6): 538-546, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29777219

RESUMO

Immune responses in tissues are constrained by the physiological properties of the tissue involved. Tissue-resident memory T cells (TRM cells) are a recently discovered lineage of T cells specialized for life and function within tissues. Emerging evidence has shown that TRM cells have a special role in the control of solid tumors. A high frequency of TRM cells in tumors correlates with favorable disease progression in patients with cancer, and studies of mice have shown that TRM cells are necessary for optimal immunological control of solid tumors. Here we describe what defines TRM cells as a separate lineage and how these cells are generated. Furthermore, we discuss the properties that allow TRM cells to operate in normal and transformed tissues, as well as implications for the treatment of patients with cancer.


Assuntos
Memória Imunológica/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Humanos , Camundongos
6.
Proc Natl Acad Sci U S A ; 121(24): e2403054121, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38838017

RESUMO

Chronic Toxoplasma gondii infection induces brain-resident CD8+ T cells (bTr), but the protective functions and differentiation cues of these cells remain undefined. Here, we used a mouse model of latent infection by T. gondii leading to effective CD8+ T cell-mediated parasite control. Thanks to antibody depletion approaches, we found that peripheral circulating CD8+ T cells are dispensable for brain parasite control during chronic stage, indicating that CD8+ bTr are able to prevent brain parasite reactivation. We observed that the retention markers CD69, CD49a, and CD103 are sequentially acquired by brain parasite-specific CD8+ T cells throughout infection and that a majority of CD69/CD49a/CD103 triple-positive (TP) CD8+ T cells also express Hobit, a transcription factor associated with tissue residency. This TP subset develops in a CD4+ T cell-dependent manner and is associated with effective parasite control during chronic stage. Conditional invalidation of Transporter associated with Antigen Processing (TAP)-mediated major histocompatibility complex (MHC) class I presentation showed that presentation of parasite antigens by glutamatergic neurons and microglia regulates the differentiation of CD8+ bTr into TP cells. Single-cell transcriptomic analyses revealed that resistance to encephalitis is associated with the expansion of stem-like subsets of CD8+ bTr. In summary, parasite-specific brain-resident CD8+ T cells are a functionally heterogeneous compartment which autonomously ensure parasite control during T. gondii latent infection and which differentiation is shaped by neuronal and microglial MHC I presentation. A more detailed understanding of local T cell-mediated immune surveillance of this common parasite is needed for harnessing brain-resident CD8+ T cells in order to enhance control of chronic brain infections.


Assuntos
Encéfalo , Linfócitos T CD8-Positivos , Diferenciação Celular , Toxoplasma , Toxoplasmose , Animais , Linfócitos T CD8-Positivos/imunologia , Toxoplasma/imunologia , Camundongos , Encéfalo/imunologia , Encéfalo/parasitologia , Diferenciação Celular/imunologia , Toxoplasmose/imunologia , Toxoplasmose/parasitologia , Infecção Latente/imunologia , Infecção Latente/parasitologia , Antígenos CD/metabolismo , Antígenos CD/imunologia , Antígenos CD/genética , Camundongos Endogâmicos C57BL , Feminino
7.
Eur J Immunol ; 54(5): e2350873, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38501878

RESUMO

Resident memory T (TRM) cells have been recently established as an important subset of memory T cells that provide early and essential protection against reinfection in the absence of circulating memory T cells. Recent findings showing that TRM expand in vivo after repeated antigenic stimulation indicate that these memory T cells are not terminally differentiated. This suggests an opportunity for in vitro TRM expansion to apply in an immunotherapy setting. However, it has also been shown that TRM may not maintain their identity and form circulating memory T cells after in vivo restimulation. Therefore, we set out to determine how TRM respond to antigenic activation in culture. Using Listeria monocytogenes and LCMV infection models, we found that TRM from the intraepithelial compartment of the small intestine expand in vitro after antigenic stimulation and subsequent resting in homeostatic cytokines. A large fraction of the expanded TRM retained their phenotype, including the expression of key TRM markers CD69 and CD103 (ITGAE). The optimal culture of TRM required low O2 pressure to maintain the expression of these and other TRM-associated molecules. Expanded TRM retained their effector capacity to produce cytokines after restimulation, but did not acquire a highly glycolytic profile indicative of effector T cells. The proteomic analysis confirmed TRM profile retention, including expression of TRM-related transcription factors, tissue retention factors, adhesion molecules, and enzymes involved in fatty acid metabolism. Collectively, our data indicate that limiting oxygen conditions supports in vitro expansion of TRM cells that maintain their TRM phenotype, at least in part, suggesting an opportunity for therapeutic strategies that require in vitro expansion of TRM.


Assuntos
Memória Imunológica , Listeria monocytogenes , Células T de Memória , Animais , Células T de Memória/imunologia , Memória Imunológica/imunologia , Camundongos , Listeria monocytogenes/imunologia , Antígenos CD/metabolismo , Antígenos CD/imunologia , Cadeias alfa de Integrinas/metabolismo , Camundongos Endogâmicos C57BL , Listeriose/imunologia , Lectinas Tipo C/metabolismo , Lectinas Tipo C/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Citocinas/metabolismo , Citocinas/imunologia , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Mucosa Intestinal/imunologia , Linfócitos T CD8-Positivos/imunologia , Intestino Delgado/imunologia , Células Cultivadas
8.
Eur J Immunol ; 53(3): e2250305, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36680414

RESUMO

The magnitude of CD8 T-cell responses against intracellular pathogens is thought to primarily depend on the expansion capacity of naïve T cells, given that their recruitment is considered optimal. In the current issue of the European Journal of Immunology [Eur. J. Immunol. 2023. 53: 000-000], Leube et al. challenge these concepts and show that the recruitment of naïve T-cell clones into primary responses can be far from complete. The failure to efficiently recruit T-cell clones occurs more frequently in case of low-affinity interactions of the T-cell receptor with cognate antigen of the pathogen. Using single-cell fate-mapping in the Lm-OVA model, the authors demonstrate that naïve T-cell clones of low affinity in contrast to those of high affinity often do not expand after pathogen encounter. These low-affinity clones are maintained as naïve CD8 T cells that can robustly respond upon secondary encounter with the same pathogen, in particular when the reencountered pathogen contains modifications resulting in improved recognition. Thus, this study indicates that the regulation of the response size of CD8 T cells is yet more elaborate than anticipated and involves control at the level of recruitment and expansion of naïve CD8 T cells.


Assuntos
Linfócitos T CD8-Positivos , Receptores de Antígenos de Linfócitos T , Células Clonais , Antígenos , Diferenciação Celular
9.
Eur J Immunol ; 53(2): e2149435, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36408791

RESUMO

Type 1 Innate Lymphoid cells (ILC1s) are tissue-resident cells that partake in the regulation of inflammation and homeostasis. A major feature of ILC1s is their ability to rapidly respond after infections. The effector repertoire of ILC1s includes the pro-inflammatory cytokines IFN-γ and TNF-α and cytotoxic mediators such as granzymes, which enable ILC1s to establish immune responses and to directly kill target cells. Recent advances in the characterization of ILC1s have considerably furthered our understanding of ILC1 development and maintenance in tissues. In particular, it has become clear how ILC1s operate independently from conventional natural killer cells, with which they share many characteristics. In this review, we discuss recent developments with regards to the differentiation, polarization, and effector maturation of ILC1s. These processes may underlie the observed heterogeneity in ILC1 populations within and between different tissues. Next, we highlight transcriptional programs that control each of the separate steps in the differentiation of ILC1s. These transcriptional programs are shared with other tissue-resident type-1 lymphocytes, such as tissue-resident memory T cells (TRM ) and invariant natural killer T cells (iNKT), highlighting that ILC1s utilize networks of transcriptional regulation that are conserved between lymphocyte lineages to respond effectively to tissue-invading pathogens.


Assuntos
Imunidade Inata , Linfócitos , Diferenciação Celular , Citocinas , Regulação da Expressão Gênica , Imunidade Inata/genética , Imunidade Inata/imunologia , Células Matadoras Naturais , Linfócitos/imunologia
10.
Eur J Immunol ; 53(2): e2249918, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36482267

RESUMO

Memory CD8+ T cells are indispensable for maintaining long-term immunity against intracellular pathogens and tumors. Despite their presence at oxygen-deprived infected tissue sites or in tumors, the impact of local oxygen pressure on memory CD8+ T cells remains largely unclear. We sought to elucidate how oxygen pressure impacts memory CD8+ T cells arising after infection with Listeria monocytogenes-OVA. Our data revealed that reduced oxygen pressure during in vitro culture switched CD8+ T cell metabolism from oxidative phosphorylation to a glycolytic phenotype. Quantitative proteomic analysis showed that limiting oxygen conditions increased the expression of glucose transporters and components of the glycolytic pathway, while decreasing TCA cycle and mitochondrial respiratory chain proteins. The altered CD8+ T cell metabolism did not affect the expansion potential, but enhanced the granzyme B and IFN-γ production capacity. In vivo, memory CD8+ T cells cultured under low oxygen pressure provided protection against bacterial rechallenge. Taken together, our study indicates that strategies of cellular immune therapy may benefit from reducing oxygen during culture to develop memory CD8+ T cells with superior effector functions.


Assuntos
Listeria monocytogenes , Listeriose , Neoplasias , Animais , Camundongos , Linfócitos T CD8-Positivos , Proteômica , Neoplasias/patologia , Oxigênio/metabolismo , Glicólise , Memória Imunológica , Camundongos Endogâmicos C57BL
11.
Nat Immunol ; 13(9): 864-71, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22885984

RESUMO

The transcriptional repressor Blimp-1 mediates the terminal differentiation of many cell types, including T cells. Here we identified Hobit (Znf683) as a previously unrecognized homolog of Blimp-1 that was specifically expressed in mouse natural killer T cells (NKT cells). Through studies of Hobit-deficient mice, we found that Hobit was essential for the formation of mature thymic NKT cells. In the periphery, Hobit repressed the accumulation of interferon-γ (IFN-γ)-producing NK1.1(lo) NKT cells at steady state. After antigenic stimulation, Hobit repressed IFN-γ expression, whereas after innate stimulation, Hobit induced granzyme B expression. Thus, reminiscent of the function of Blimp-1 in other lymphocytes, Hobit controlled the maintenance of quiescent, fully differentiated NKT cells and regulated their immediate effector functions.


Assuntos
Diferenciação Celular/genética , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/imunologia , Sequência de Aminoácidos , Animais , Diferenciação Celular/imunologia , Citometria de Fluxo , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Filogenia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética
12.
Eur J Immunol ; 52(7): 1095-1111, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35389518

RESUMO

Tissue-resident memory T cells (Trm) are retained in peripheral tissues after infection for enhanced protection against secondary encounter with the same pathogen. We have previously shown that the transcription factor Hobit and its homolog Blimp-1 drive Trm development after viral infection, but how and when these transcription factors mediate Trm formation remains poorly understood. In particular, the major impact of Blimp-1 in regulating several aspects of effector T-cell differentiation impairs study of its specific role in Trm development. Here, we used the restricted expression of Hobit in the Trm lineage to develop mice with a conditional deletion of Blimp-1 in Trm, allowing us to specifically investigate the role of both transcription factors in Trm differentiation. We found that Hobit and Blimp-1 were required for the upregulation of CD69 and suppression of CCR7 and S1PR1 on virus-specific Trm precursors after LCMV infection, underlining a role in their retention within tissues. The early impact of Hobit and Blimp-1 favored Trm formation and prevented the development of circulating memory T cells. Thus, our findings highlight a role of Hobit and Blimp-1 at the branching point of circulating and resident memory lineages by suppressing tissue egress of Trm precursors early during infection.


Assuntos
Linfócitos T CD8-Positivos , Memória Imunológica , Coriomeningite Linfocítica , Vírus da Coriomeningite Linfocítica , Fator 1 de Ligação ao Domínio I Regulador Positivo , Fatores de Transcrição , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
13.
Eur J Immunol ; 51(6): 1310-1324, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33837521

RESUMO

Immunological memory equips our immune system to respond faster and more effectively against reinfections. This acquired immunity was originally attributed to long-lived, memory T and B cells with body wide access to peripheral and secondary lymphoid tissues. In recent years, it has been realized that both innate and adaptive immunity to a large degree depends on resident immune cells that act locally in barrier tissues including tissue-resident memory T cells (Trm). Here, we will discuss the phenotype of these Trm in mice and humans, the tissues and niches that support them, and their function, plasticity, and transcriptional control. Their unique properties enable Trm to achieve long-lived immunological memory that can be deposited in nearly every organ in response to acute and persistent infection, and in response to cancer. However, Trm may also induce substantial immunopathology in allergic and autoimmune disease if their actions remain unchecked. Therefore, inhibitory and activating stimuli appear to balance the actions of Trm to ensure rapid proinflammatory responses upon infection and to prevent damage to host tissues under steady state conditions.


Assuntos
Doenças Autoimunes/imunologia , Hipersensibilidade/imunologia , Inflamação/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Plasticidade Celular , Humanos , Memória Imunológica , Camundongos
14.
Eur J Immunol ; 51(1): 151-166, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32762051

RESUMO

Tissue-resident memory CD8+ T cells (TRM ) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (TCM ) and effector memory CD8+ T cells (TEM ) also contribute to tissue recall responses, but their potential to form mucosal TRM remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of TCM and TEM at mucosal sites. Donor TCM and TEM exhibited robust systemic recall responses, but only limited accumulation in the small intestine, consistent with reduced expression of tissue-homing and -retention molecules. Murine and human circulating memory T cells also exhibited limited CD103 upregulation following TGF-ß stimulation. Upon pathogen clearance, TCM and TEM readily gave rise to secondary TEM . TCM also formed secondary central memory in lymphoid tissues and TRM in internal tissues, for example, the liver. Both TCM and TEM failed to substantially contribute to resident mucosal memory in the small intestine, while activated intestinal TRM , but not liver TRM , efficiently reformed CD103+ TRM . Our findings demonstrate that circulating TCM and TEM are limited in generating mucosal TRM upon reinfection. This may pose important implications on cell therapy and vaccination strategies employing memory CD8+ T cells for protection at mucosal sites.


Assuntos
Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas , Memória Imunológica , Cadeias alfa de Integrinas/imunologia , Imunidade Adaptativa , Transferência Adotiva , Animais , Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Feminino , Humanos , Cadeias alfa de Integrinas/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Intestino Delgado/citologia , Intestino Delgado/imunologia , Ativação Linfocitária , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucosa/citologia , Mucosa/imunologia , Fator de Crescimento Transformador beta/imunologia
15.
Eur J Immunol ; 50(10): 1515-1524, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32390174

RESUMO

Invariant natural killer T cells (iNKT) constitute up to 50% of liver lymphocytes and contribute to immunosurveillance as well as pathogenesis of the liver. Systemic activation of iNKT cells induces acute immune-mediated liver injury. However, how tissue damage events regulate iNKT cell function and homeostasis remains unclear. We found that specifically tissue-resident iNKT cells in liver and spleen express the tissue-damage receptor P2RX7 and the P2RX7-activating ectoenzyme ARTC2. P2RX7 expression restricted formation of iNKT cells in the liver suggesting that liver iNKT cells are actively restrained under homeostatic conditions. Deliberate activation of P2RX7 in vivo by exogenous NAD resulted in a nearly complete iNKT cell ablation in liver and spleen in a P2RX7-dependent manner. Tissue damage generated by acetaminophen-induced liver injury reduced the number of iNKT cells in the liver. The tissue-damage-induced iNKT cell depletion was driven by P2RX7 and localized to the site of injury, as iNKT cells in the spleen remained intact. The depleted liver iNKT cells reconstituted only slowly compared to other lymphocytes such as regulatory T cells. These findings suggest that tissue-damage-mediated depletion of iNKT cells acts as a feedback mechanism to limit iNKT cell-induced pathology resulting in the establishment of a tolerogenic environment.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Fígado/patologia , Células T Matadoras Naturais/fisiologia , Receptores Purinérgicos P2X7/metabolismo , Acetaminofen/administração & dosagem , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Tolerância Imunológica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Purinérgicos P2X7/genética
16.
Eur J Immunol ; 49(6): 853-872, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30891737

RESUMO

BM has been put forward as a major reservoir for memory CD8+  T cells. In order to fulfill that function, BM should "store" memory CD8+ T cells, which in biological terms would require these "stored" memory cells to be in disequilibrium with the circulatory pool. This issue is a matter of ongoing debate. Here, we unequivocally demonstrate that murine and human BM harbors a population of tissue-resident memory CD8+ T (TRM ) cells. These cells develop against various pathogens, independently of BM infection or local antigen recognition. BM CD8+ TRM cells share a transcriptional program with resident lymphoid cells in other tissues; they are polyfunctional cytokine producers and dependent on IL-15, Blimp-1, and Hobit. CD8+ TRM cells reside in the BM parenchyma, but are in close contact with the circulation. Moreover, this pool of resident T cells is not size-restricted and expands upon peripheral antigenic re-challenge. This works extends the role of the BM in the maintenance of CD8+ T cell memory to include the preservation of an expandable reservoir of functional, non-recirculating memory CD8+ T cells, which develop in response to a large variety of peripheral antigens.


Assuntos
Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL
17.
Immunity ; 35(1): 97-108, 2011 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-21763160

RESUMO

CD70 and CD27 are costimulatory molecules that provide essential signals for the expansion and differentiation of CD8(+) T cells. Here, we show that CD27-driven costimulation lowered the threshold of T cell receptor activation on CD8(+) T cells and enabled responses against low-affinity antigens. Using influenza infection to study in vivo consequences, we found that CD27-driven costimulation promoted a CD8(+) T cell response of overall low affinity. These qualitative effects of CD27 on T cell responses were maintained into the memory phase. On a clonal level, CD27-driven costimulation established a higher degree of variety in memory CD8(+) T cells. The benefit became apparent when mice were reinfected, given that CD27 improved CD8(+) T cell responses against reinfection with viral variants, but not with identical virus. We propose that CD27-driven costimulation is a strategy to generate memory clones that have potential reactivity to a wide array of mutable pathogens.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Animais , Variação Antigênica , Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Células Clonais , Humanos , Memória Imunológica , Vírus da Influenza A/patogenicidade , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade do Receptor de Antígeno de Linfócitos T/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
18.
Eur J Immunol ; 48(10): 1644-1662, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30051906

RESUMO

CD8 T cells acquire cytotoxic molecules including granzyme B during effector differentiation. Both tissue-resident memory CD8 T cells (Trm) and circulating CD45RA+ effector-type T cells (Temra) cells have the ability to retain granzyme B protein expression into the memory phase, but it is unclear how this persistence of cytolytic activity is regulated during steady state. Previously, we have described that the transcriptional regulators Hobit and Blimp-1 have overlapping target genes that include granzyme B, but their impact on the regulation of cytotoxicity in Trm and Temra cells during homeostasis has remained unclear. We examined the expression regulation of Hobit and Blimp-1 in murine and human CD8 T-cells to determine their timeframe of activity. While Blimp-1 mRNA was expressed throughout effector and memory T cells, Blimp-1 protein, was only transiently expressed during the effector stage. In contrast, Hobit mRNA and protein expression was stably maintained during quiescence, but downregulated after activation. Notably, Blimp-1 was required for expression of granzyme B in murine effector T cells and Trm, while Hobit specifically regulated granzyme B in murine Trm during the memory phase. These findings suggest that Blimp-1 initiates cytotoxic effector function and that Hobit maintains cytotoxicity in a deployment-ready modus in Trm.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fatores de Transcrição/genética , Animais , Células Cultivadas , Regulação da Expressão Gênica/imunologia , Granzimas/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
19.
Immunity ; 32(6): 754-65, 2010 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-20620942

RESUMO

The adaptive immune system generates protective T cell responses via a poorly understood selection mechanism that favors expansion of clones with optimal affinity for antigen. Here we showed that upon T cell activation, the proapoptotic molecule Noxa (encoded by Pmaip1) and its antagonist Mcl-1 were induced. During an acute immune response against influenza or ovalbumin, Pmaip1(-/-) effector T cells displayed decreased antigen affinity and functionality. Molecular analysis of influenza-specific T cells revealed persistence of many subdominant clones in the Pmaip1(-/-) effector pool. When competing for low-affinity antigen, Pmaip1(-/-) TCR transgenic T cells had a survival advantage in vitro, resulting in increased numbers of effector cells in vivo. Mcl-1 protein stability was controlled by T cell receptor (TCR) affinity-dependent interleukin-2 signaling. These results establish a role for apoptosis early during T cell expansion, based on antigen-driven competition and survival of the fittest T cells.


Assuntos
Apoptose/imunologia , Ativação Linfocitária/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Separação Celular , Células Clonais , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica , Immunoblotting , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Sequência 1 de Leucemia de Células Mieloides , Receptores de Antígenos de Linfócitos T/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia
20.
PLoS Pathog ; 11(3): e1004675, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25738498

RESUMO

Chronic infections are characterized by the inability to eliminate the persisting pathogen and often associated with functional impairment of virus-specific T-cell responses. Costimulation through Glucocorticoid-induced TNFR-related protein (GITR) can increase survival and function of effector T cells. Here, we report that constitutive expression of GITR-ligand (GITRL) confers protection against chronic lymphocytic choriomeningitis virus (LCMV) infection, accelerating recovery without increasing pathology. Rapid viral clearance in GITRL transgenic mice coincided with increased numbers of poly-functional, virus-specific effector CD8+ T cells that expressed more T-bet and reduced levels of the rheostat marker PD-1. GITR triggering also boosted the helper function of virus-specific CD4 T cells already early in the infection, as was evidenced by increased IL-2 and IFNγ production, and more expression of CD40L and T-bet. Importantly, CD4-depletion experiments revealed that the expanded pool of virus-specific effector CD8 T cells and the ensuing viral clearance in LCMV-infected GITRL tg mice was entirely dependent on CD4 T cells. We found no major differences for NK cell and regulatory T cell responses, whereas the humoral response to the virus was increased in GITRL tg mice, but only in the late phase of the infection when the virus was almost eradicated. Based on these findings, we conclude that enhanced GITR-triggering mediates its protective, anti-viral effect on the CD8 T cell compartment by boosting CD4 T cell help. As such, increasing costimulation through GITR may be an attractive strategy to increase anti-viral CTL responses without exacerbating pathology, in particular to persistent viruses such as HIV and HCV.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Imunidade Celular , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Ligante de CD40/genética , Ligante de CD40/imunologia , Linfócitos T CD8-Positivos/patologia , Doença Crônica , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/patologia , Camundongos , Camundongos Transgênicos , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Linfócitos T Auxiliares-Indutores/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA