RESUMO
Interleukin-7 (IL-7) is considered a critical regulator of memory CD8+ T cell homeostasis, but this is primarily based on analysis of circulating and not tissue-resident memory (TRM) subsets. Furthermore, the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Using inducible deletion, we found that Il7ra loss had only a modest effect on persistence of circulating memory and TRM subsets and that IL-7Rα was primarily required for normal basal proliferation. Loss of IL-15 signaling imposed heightened IL-7Rα dependence on memory CD8+ T cells, including TRM populations previously described as IL-15-independent. In the absence of IL-15 signaling, IL-7Rα was upregulated, and loss of IL-7Rα signaling reduced proliferation in response to IL-15, suggesting cross-regulation in memory CD8+ T cells. Thus, across subsets and tissues, IL-7 and IL-15 act in concert to support memory CD8+ T cells, conferring resilience to altered availability of either cytokine.
RESUMO
The mechanisms that make and break CD8+ T cell tolerance to self-antigens remain unclear. In this issue of Immunity, Van Der Byl et al. show that tolerant CD8+ T cells rapidly adopt an epigenetically and transcriptionally distinct cell state and exhibit impaired protein translation. Breaking tolerance requires both inflammation and increased antigen exposure to augment MYC expression and restore translation.
Assuntos
Linfócitos T CD8-Positivos , Tolerância Imunológica , Linfócitos T CD8-Positivos/imunologia , Tolerância Imunológica/imunologia , Animais , Humanos , Epigênese Genética/imunologia , Camundongos , Biossíntese de Proteínas/imunologiaRESUMO
Lung group 2 innate lymphoid cells (ILC2s) control the nature of immune responses to airway allergens. Some microbial products, including those that stimulate interferons, block ILC2 activation, but whether this occurs after natural infections or causes durable ILC2 inhibition is unclear. In the present study, we cohoused laboratory and pet store mice as a model of physiological microbial exposure. Laboratory mice cohoused for 2 weeks had impaired ILC2 responses and reduced lung eosinophilia to intranasal allergens, whereas these responses were restored in mice cohoused for ≥2 months. ILC2 inhibition at 2 weeks correlated with increased interferon receptor signaling, which waned by 2 months of cohousing. Reinduction of interferons in 2-month cohoused mice blocked ILC2 activation. These findings suggest that ILC2s respond dynamically to environmental cues and that microbial exposures do not control long-term desensitization of innate type 2 responses to allergens.
Assuntos
Alérgenos , Imunidade Inata , Camundongos , Animais , Linfócitos , Citocinas , Pulmão , Interferons , Interleucina-33RESUMO
Laboratory mice comprise an expeditious model for preclinical vaccine testing; however, vaccine immunogenicity in these models often inadequately translates to humans. Reconstituting physiologic microbial experience to specific pathogen-free (SPF) mice induces durable immunological changes that better recapitulate human immunity. We examined whether mice with diverse microbial experience better model human responses post vaccination. We co-housed laboratory mice with pet-store mice, which have varied microbial exposures, and then assessed immune responses to influenza vaccines. Human transcriptional responses to influenza vaccination are better recapitulated in co-housed mice. Although SPF and co-housed mice were comparably susceptible to acute influenza infection, vaccine-induced humoral responses were dampened in co-housed mice, resulting in poor control upon challenge. Additionally, protective heterosubtypic T cell immunity was compromised in co-housed mice. Because SPF mice exaggerated humoral and T cell protection upon influenza vaccination, reconstituting microbial experience in laboratory mice through co-housing may better inform preclinical vaccine testing.
Assuntos
Imunogenicidade da Vacina , Vacinas contra Influenza/imunologia , Animais , Feminino , Humanos , Imunidade Humoral , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , VacinaçãoRESUMO
Self-specific CD8+T cells can escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8+ T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice expressing or lacking this enzyme (due to deficiency in Dct, which encodes Trp2). Phenotypic and gene expression profiles of pre-immune Trp2/Kb-specific cells were similar; the size of this population was only slightly reduced in wild-type (WT) compared to Dct-deficient (Dct-/-) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/Kb-specific cells showed blunted expansion and less readily differentiated into a CD25+proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/Kb-specific cells mediated vitiligo much less efficiently. Hence, CD8+ T cell self-specificity is poorly predicted by precursor frequency, phenotype, or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Tolerância a Antígenos Próprios , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Feminino , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vitiligo/imunologiaRESUMO
Extracellular ATP (eATP) is an ancient 'danger signal' used by eukaryotes to detect cellular damage1. In mice and humans, the release of eATP during inflammation or injury stimulates both innate immune activation and chronic pain through the purinergic receptor P2RX72-4. It is unclear, however, whether this pathway influences the generation of immunological memory, a hallmark of the adaptive immune system that constitutes the basis of vaccines and protective immunity against re-infection5,6. Here we show that P2RX7 is required for the establishment, maintenance and functionality of long-lived central and tissue-resident memory CD8+ T cell populations in mice. By contrast, P2RX7 is not required for the generation of short-lived effector CD8+ T cells. Mechanistically, P2RX7 promotes mitochondrial homeostasis and metabolic function in differentiating memory CD8+ T cells, at least in part by inducing AMP-activated protein kinase. Pharmacological inhibitors of P2RX7 provoked dysregulated metabolism and differentiation of activated mouse and human CD8+ T cells in vitro, and transient P2RX7 blockade in vivo ameliorated neuropathic pain but also compromised production of CD8+ memory T cells. These findings show that activation of P2RX7 by eATP provides a common currency that both alerts the nervous and immune system to tissue damage, and promotes the metabolic fitness and survival of the most durable and functionally relevant memory CD8+ T cell populations.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica , Receptores Purinérgicos P2X7/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Ativação Enzimática , Feminino , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/fisiologia , Receptores Purinérgicos P2X7/deficiência , Receptores Purinérgicos P2X7/genéticaRESUMO
Lung complications are a major cause of rheumatoid arthritis-related mortality. Involvement of gut microbiota in lung diseases by the gut-lung axis has been widely observed, but the underlying mechanism remains mostly unknown. Using an autoimmune arthritis model, we show that a constituent of the gut microbiota, segmented filamentous bacteria (SFB), distantly provoke lung pathology. SFB induce autoantibodies in lung during the pre-arthritic phase, and SFB-dependent lung pathology requires the T helper 17 (Th17) responses. SFB-induced gut Th17 cells are preferentially recruited to lung over spleen due to robust expression in the lung of the Th17 chemoattractant, CCL20. Additionally, we found that in peripheral tissues, SFB selectively expand dual T cell receptor (TCR)-expressing Th17 cells recognizing both an SFB epitope and self-antigen, thus augmenting autoimmunity. This study reveals mechanisms for commensal-mediated gut-lung crosstalk and dual TCR-based autoimmunity.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/microbiologia , Autoimunidade , Bactérias/imunologia , Microbioma Gastrointestinal/imunologia , Pulmão/imunologia , Células Th17/imunologia , Animais , Apoptose/imunologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Autoanticorpos , Bactérias/patogenicidade , Diferenciação Celular/imunologia , Proliferação de Células , Quimiocina CCL20/metabolismo , Modelos Animais de Doenças , Fezes/microbiologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Baço , Simbiose , Células Th17/metabolismoRESUMO
B cells are unique antigen-presenting cells because their antigen presentation machinery is closely tied to the B cell receptor. Autoreactive thymic B cells can efficiently present cognate self-antigens to mediate CD4+ T cell-negative selection. However, the nature of thymocyte-thymic B cell interaction and how this interaction affects the selection of thymic B cell repertoire and, in turn, the T cell repertoire are not well understood. Here we demonstrate that a large percentage of thymic B cells have undergone class switching intrathymically. Thymic B cell class switching requires cognate interaction with specific T cells. Class-switched thymic B cells have a distinct repertoire compared with unswitched thymic B cells or splenic B cells. Particularly, autoreactive B cell specificities preferentially expand in the thymus by undergoing class switching, and these enriched, class-switched autoreactive thymic B cells play an important role in CD4 T cell tolerance.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Tolerância Central/imunologia , Switching de Imunoglobulina/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/metabolismo , Autoantígenos/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Humanos , Ativação Linfocitária/imunologia , Camundongos , Timócitos/imunologia , Timócitos/metabolismoRESUMO
The bacterial community that colonizes mucosal surfaces helps shape the development and function of the immune system. The K/BxN autoimmune arthritis model is dependent on the microbiota, and particularly on segmented filamentous bacteria, for the autoimmune phenotype. The mechanisms of how the gut microbiota affects arthritis development are not well understood. In this study, we investigate the contribution of two T cell subsets, Th17 and follicular helper T (Tfh), to arthritis and how microbiota modulates their differentiation. Using genetic approaches, we demonstrate that IL-17 is dispensable for arthritis. Antibiotic treatment inhibits disease in IL-17-deficient animals, suggesting that the gut microbiota regulates arthritis independent of Th17 cells. In contrast, conditional deletion of Bcl6 in T cells blocks Tfh cell differentiation and arthritis development. Furthermore, Tfh cell differentiation is defective in antibiotic-treated mice. Taken together, we conclude that gut microbiota regulates arthritis through Tfh but not Th17 cells. These findings have implications in our understanding of how environmental factors contribute to the development of autoimmune diseases.
Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Microbioma Gastrointestinal/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Th17/imunologia , Animais , Artrite Experimental/imunologia , Diferenciação Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Centro Germinativo/citologia , Centro Germinativo/imunologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Mucosa/citologia , Mucosa/imunologia , Proteínas Proto-Oncogênicas c-bcl-6RESUMO
The antimalarial drug artemisinin and its derivatives exhibit potent immunosuppressive activity in several autoimmune disease models, however the mechanisms are not well-understood. This study was designed to investigate the therapeutic effects and the underlying mechanisms of the artemisinin analog artesunate using the K/BxN mouse model of rheumatoid arthritis. The well-studied disease mechanisms of K/BxN model allowed us to pinpoint the effect of artesunate on disease. Artesunate treatment prevented arthritis development in young K/BxN mice by inhibiting germinal center (GC) formation and production of autoantibodies. In adult K/BxN mice with established arthritis, artesunate diminished GC B cells in a few days. However, artesunate did not affect the follicular helper T cells (Tfh). In contrast to the spontaneous K/BxN model, artesunate treatment exerted minor influence on K/BxN serum transfer induced arthritis suggesting that artesunate has minimal effect on inflammatory responses downstream of antibody production. Finally, we showed that artesunate preferentially inhibits proliferating GC B cells. These results identify GC B cells as a target of artesunate and provide a new rationale for using artemisinin analogues to treat autoimmune diseases mediated by autoantibodies.
Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Artrite Experimental/tratamento farmacológico , Linfócitos B/citologia , Centro Germinativo/citologia , Animais , Artesunato , Artrite Experimental/prevenção & controle , Artrite Reumatoide/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Centro Germinativo/efeitos dos fármacos , Centro Germinativo/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Distribuição Aleatória , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
IL-21 is a pluripotent cytokine that regulates B cell and plasma cell differentiation and is thought be an autocrine factor for follicular helper T cell (T(FH)) and Th17 differentiation. Although IL-21 has been implicated in autoimmune diseases, its relevant cellular source and target cells have not been well characterized. We investigated this issue in the K/BxN mouse model of autoimmune arthritis. Adoptive transfer of KRN-transgenic CD4⺠T cells into appropriate hosts drives germinal center (GC) formation and autoantibody production against glucose-6-phosphate isomerase, leading to joint inflammation and destruction. By comparing transfer of T or B cells deficient in IL-21 or IL-21R, we were able to dissect the contribution of each cell type. T cells deficient in IL-21 did not induce GC formation or autoantibody production, but they went through normal T(FH) differentiation. However, T cells lacking IL-21R induced Ab titers, GC B cell frequency, and arthritis development similar to wild-type T cells, suggesting that IL-21 is not required for T(FH) differentiation and function. IL-21 acts on B cells, because IL-21R expression on B cells was required to induce disease. In contrast, Th17 cells, a T cell subset that also produces IL-21 and can provide help to B cells, are not required for the GC response and arthritis. These data have implications in developing effective therapies for rheumatoid arthritis and other Ab-mediated autoimmune diseases.
Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Interleucinas/imunologia , Transferência Adotiva , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Linfócitos B/citologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imuno-Histoquímica , Interleucinas/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores de Interleucina-21/imunologia , Receptores de Interleucina-21/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
The HIV pandemic disproportionately affects women, with most infections acquired through receptive vaginal sex. Although the target cells by which HIV establishes infection in the female genital tract remain poorly defined, it is known that immune activation results in CD4(+) T cells with enhanced susceptibility, as does expression of the mucosal integrin α4ß7 and the HIV coreceptor CCR5. Blood and cervical cytobrush specimens were collected from female sex workers (FSWs) in Nairobi, Kenya. Genital infection diagnostics were performed, T cell populations were defined by multiparameter flow cytometry based on their expression of surface receptors relevant to mucosal homing and/or HIV acquisition, and cytokine production was assayed by intracellular cytokine staining. The integrin α4ß7 was expressed on 26.0% of cervical CD4(+) T cells, and these cells were more likely to express both the HIV coreceptor CCR5 (p < 0.0001) and the early activation marker CD69 (p < 0.0001) but not CXCR4 (p = 0.34). Cervical Th17 frequencies were enhanced compared with blood (7.02 versus 1.24%; p < 0.0001), and cervical IL-17A(+) CD4(+) T cells preferentially coexpressed α4ß7 and CCR5. Expression of IFN-γ and IL-22 was greater in cervical Th17 cells than in blood Th17 cells. In keeping with the hypothesis that these cells are preferential HIV targets, gp120 preferentially bound CCR5(+) cervical T cells, and cervical Th17 cells were almost completely depleted in HIV(+) FSWs compared with HIV(-) FSWs. In summary, a subset of Th17 CD4(+) T cells in the cervical mucosa coexpresses multiple HIV susceptibility markers; their dramatic depletion after HIV infection suggests that these may serve as key target cells during HIV transmission.
Assuntos
Colo do Útero/imunologia , Infecções por HIV/transmissão , Imunidade nas Mucosas/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Adulto , Biomarcadores/análise , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Separação Celular , Colo do Útero/citologia , Colo do Útero/metabolismo , Citocinas/análise , Citocinas/biossíntese , Citocinas/imunologia , Suscetibilidade a Doenças/imunologia , Feminino , Citometria de Fluxo , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Humanos , Integrinas/análise , Integrinas/biossíntese , Integrinas/imunologia , Interferon gama/análise , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-17/análise , Interleucina-17/biossíntese , Interleucina-17/imunologia , Receptores CCR5/análise , Receptores CCR5/biossíntese , Receptores CCR5/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/virologia , Células Th17/metabolismo , Células Th17/virologiaRESUMO
Mucosal transmission of HIV is inefficient. The virus must breach physical barriers before it infects mucosal CD4+ T cells. Low-level viral replication occurs initially in mucosal CD4+ T cells, but within days high-level replication occurs in Peyer's patches, the gut lamina propria and mesenteric lymph nodes. Understanding the early events in HIV transmission may provide valuable information relevant to the development of an HIV vaccine. The viral quasispecies in a donor contracts through a genetic bottleneck in the recipient, such that, in low-risk settings, infection is frequently established by a single founder virus. Early-transmitting viruses in subtypes A and C mucosal transmission tend to encode gp120s with reduced numbers of N-linked glycosylation sites at specific positions throughout the V1-V4 domains, relative to typical chronically replicating isolates in the donor quasispecies. The transmission advantage gained by the absence of these N-linked glycosylation sites is unknown. Using primary α4ß7/CD4+ T cells and a flow-cytometry based steady-state binding assay we show that the removal of transmission-associated N-linked glycosylation sites results in large increases in the specific reactivity of gp120 for integrin-α4ß7. High-affinity for integrin α4ß7, although not found in many gp120s, was observed in early-transmitting gp120s that we analyzed. Increased α4ß7 affinity is mediated by sequences encoded in gp120 V1/V2. α4ß7-reactivity was also influenced by N-linked glycosylation sites located in C3/V4. These results suggest that the genetic bottleneck that occurs after transmission may frequently involve a relative requirement for the productive infection of α4ß7+/CD4+ T cells. Early-transmitting gp120s were further distinguished by their dependence on avidity-effects to interact with CD4, suggesting that these gp120s bear unusual structural features not present in many well-characterized gp120s derived from chronically replicating viruses. Understanding the structural features that characterize early-transmitting gp120s may aid in the design of an effective gp120-based subunit vaccine.