RESUMO
Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-ß (IFNα/ß)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/ß or CD40 alone. These responses are critical for the acquisition of antiviral CD8+ T cell effector function, and their activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses.
Assuntos
Antivirais , COVID-19 , Humanos , Calibragem , Células Apresentadoras de Antígenos , Linfócitos T CD8-Positivos , Antígenos CD40 , Interferon-alfa , Linfócitos T CD4-PositivosRESUMO
Tissues such as the skin and mucosae are frequently exposed to microbial pathogens. Infectious agents must be quickly and efficiently controlled by our immune system, but the low frequency of naive T cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues; this process, combined with inflammatory signals, ensures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell numbers together with altered migratory patterns of memory T cells can greatly improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (TCM), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (TEM), which broadly migrate between peripheral tissues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (TRM), and emphasize the potential differences between the migratory patterns of CD4(+) and CD8(+) T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer.
Assuntos
Movimento Celular/imunologia , Memória Imunológica , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Adaptação Fisiológica/imunologia , Animais , Humanos , Subpopulações de Linfócitos T/classificação , Distribuição Tecidual/imunologiaRESUMO
Although tissue-resident memory T cells (TRM cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin TRM cells engaged virus-infected cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary TRM cells formed from pre-existing TRM cells, as well as from precursors recruited from the circulation. Newly recruited antigen-specific or bystander TRM cells were generated in the skin without displacement of the pre-existing TRM cell pool. Thus, pre-existing skin TRM cell populations are not displaced after subsequent infections, which enables multiple TRM cell specificities to be stably maintained within the tissue.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Pele/imunologia , Animais , Proliferação de Células/fisiologia , Herpes Simples/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8+ T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the same model CD8+ T cell epitope to the C-termini of different endogenous gene products. Targeting melanosomal proteins or oncogenic CDK4R24C (Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specific CD8+ T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directed against melanosomal proteins, but not CDK4R24C, promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4R24C antigen persistence was associated with an interferon-high and T-cell-rich tumor microenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus, the choice of target antigen determines the phenotype and immune contexture of recurrent melanomas, with implications to the design of cancer immunotherapies.
Assuntos
Transferência Adotiva/métodos , Linfócitos T CD8-Positivos/transplante , Epitopos de Linfócito T/imunologia , Melanoma/imunologia , Melanoma/terapia , Evasão Tumoral/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Terapia Baseada em Transplante de Células e Tecidos/métodos , Epitopos de Linfócito T/genética , Técnicas de Inativação de Genes , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/citologia , Células Mieloides/imunologia , Microambiente Tumoral/imunologiaRESUMO
Lymphocytes are essential in innate and adaptive immunity. Recent insights suggest that some innate lymphocytes execute functions with adaptive characteristics, while adaptive lymphocytes can operate in ways reminiscent of innate cells. Rather than partitioning lymphocytes according to the type of effector function they execute, we propose that a relevant discrimination relates to the existence of conventional T cells in a naive state. The naive state can be seen as an actively repressed condition that supports T cell diversity and enables the flexible differentiation of effector cells in a manner that best addresses the antigenic challenge. We discuss these considerations in the context of the relative roles of innate lymphoid cells and antigen-experienced T cells in the immune system.
Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Receptores de Antígenos/imunologia , Animais , Diferenciação Celular/imunologia , Células Clonais/imunologia , Células Clonais/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Linfócitos/citologia , Linfócitos/metabolismo , Modelos Imunológicos , Receptores de Antígenos/metabolismoRESUMO
Interactions with the microbiota influence many aspects of immunity, including immune cell development, differentiation, and function. Here, we examined the impact of the microbiota on CD8+ T cell memory. Antigen-activated CD8+ T cells transferred into germ-free mice failed to transition into long-lived memory cells and had transcriptional impairments in core genes associated with oxidative metabolism. The microbiota-derived short-chain fatty acid (SCFA) butyrate promoted cellular metabolism, enhanced memory potential of activated CD8+ T cells, and SCFAs were required for optimal recall responses upon antigen re-encounter. Mechanistic experiments revealed that butyrate uncoupled the tricarboxylic acid cycle from glycolytic input in CD8+ T cells, which allowed preferential fueling of oxidative phosphorylation through sustained glutamine utilization and fatty acid catabolism. Our findings reveal a role for the microbiota in promoting CD8+ T cell long-term survival as memory cells and suggest that microbial metabolites guide the metabolic rewiring of activated CD8+ T cells to enable this transition.
Assuntos
Butiratos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Ácidos Graxos Voláteis/metabolismo , Memória Imunológica , Microbiota/imunologia , Transferência Adotiva , Animais , Antígenos/imunologia , Diferenciação Celular , Células Cultivadas , Glicólise , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , OxirreduçãoRESUMO
Adipose tissue is an energy store and a dynamic endocrine organ1,2. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism3,4. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes5,6. Regulatory T (Treg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT7-9. Here we uncover pronounced sexual dimorphism in Treg cells in the VAT. Male VAT was enriched for Treg cells compared with female VAT, and Treg cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of Treg cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of Treg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident Treg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in Treg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.
Assuntos
Hormônios Esteroides Gonadais/metabolismo , Gordura Intra-Abdominal/imunologia , Caracteres Sexuais , Linfócitos T Reguladores/imunologia , Androgênios/metabolismo , Animais , Quimiocina CCL2/imunologia , Cromatina/genética , Feminino , Regulação da Expressão Gênica , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-33/imunologia , Gordura Intra-Abdominal/metabolismo , Masculino , Camundongos , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , RNA-Seq , Receptores CCR2/metabolismo , Células Estromais/citologia , Células Estromais/imunologia , Células Estromais/metabolismo , Linfócitos T Reguladores/metabolismo , Transcrição GênicaRESUMO
Tissue-resident memory T cells (T(RM) cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103(+)CD8(+) T(RM) cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-ß (TGF-ß) was required for the formation of these long-lived memory cells. Notably, differentiation into T(RM) cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.
Assuntos
Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Cadeias alfa de Integrinas/imunologia , Transdução de Sinais/imunologia , Pele/imunologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Citometria de Fluxo , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-15/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/imunologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Pele/metabolismo , Pele/virologia , Transcriptoma/genética , Transcriptoma/imunologiaRESUMO
Panel j was inadvertently labelled as panel k in the caption to Fig. 4. Similarly, 'Fig. 4k' should have been 'Fig. 4j' in the sentence beginning 'TNF-α-deficient gBT-I cells were '. In addition, the surname of author Umaimainthan Palendira was misspelled 'Palendria'. These errors have been corrected online.
RESUMO
The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication1. Clinical and experimental data suggest that the latter mode of control-termed cancer-immune equilibrium1-can be maintained for prolonged periods of time, possibly up to several decades2-4. Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses that maintain cancer-immune equilibrium in these tissue compartments remain unclear. Here, using a mouse model of transplantable cutaneous melanoma5, we show that tissue-resident memory CD8+ T cells (TRM cells) promote a durable melanoma-immune equilibrium that is confined to the epidermal layer of the skin. A proportion of mice (~40%) transplanted with melanoma cells remained free of macroscopic skin lesions long after epicutaneous inoculation, and generation of tumour-specific epidermal CD69+ CD103+ TRM cells correlated with this spontaneous disease control. By contrast, mice deficient in TRM formation were more susceptible to tumour development. Despite being tumour-free at the macroscopic level, mice frequently harboured melanoma cells in the epidermal layer of the skin long after inoculation, and intravital imaging revealed that these cells were dynamically surveyed by TRM cells. Consistent with their role in melanoma surveillance, tumour-specific TRM cells that were generated before melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of TRM cells triggered tumour outgrowth in a proportion (~20%) of mice with occult melanomas, demonstrating that TRM cells can actively suppress cancer progression. Our results show that TRM cells have a fundamental role in the surveillance of subclinical melanomas in the skin by maintaining cancer-immune equilibrium. As such, they provide strong impetus for exploring these cells as targets of future anticancer immunotherapies.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Homeostase/imunologia , Memória Imunológica/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Pele/imunologia , Idoso , Animais , Progressão da Doença , Epiderme/imunologia , Epiderme/patologia , Feminino , Humanos , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transplante de Neoplasias , Pele/patologia , Neoplasias Cutâneas/patologiaRESUMO
Although adoptive T-cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T-cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling, thereby enhancing both CAR T-cell activation and homing to CXCL9/10-expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell-mediated anti-tumour immunity and CAR T-cell therapy against solid tumours.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Neoplasias/terapia , Proteína Tirosina Fosfatase não Receptora Tipo 2/fisiologia , Receptor ErbB-2/fisiologia , Receptores de Antígenos de Linfócitos T/imunologia , Transferência Adotiva , Animais , Apresentação de Antígeno/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neoplasias/genética , Neoplasias/imunologia , Transdução de SinaisRESUMO
Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-γ (IFN-γ) secretion by noncognate memory CD8(+) T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8α(+) DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL-18) and IL-1ß, only IL-18 was required for IFN-γ production by memory CD8(+) T cells. Conversely, only the release of IL-1ß, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity.
Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Células Dendríticas/imunologia , Memória Imunológica , Inflamassomos/imunologia , Interferon gama/imunologia , Animais , Flagelina/imunologia , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Camundongos , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Salmonelose Animal/imunologia , Salmonella typhimurium/imunologia , Transdução de Sinais/imunologia , Baço/imunologia , Receptores Toll-Like/imunologia , Infecções por Yersinia pseudotuberculosis/imunologiaRESUMO
BACKGROUND: CD4+ (cluster of differentation) and CD8+ T cells are increased in the ocular fluids of patients with neovascular retinopathy, yet their role in the disease process is unknown. METHODS: We describe how CD8+ T cells migrate into the retina and contribute to pathological angiogenesis by releasing cytokines and cytotoxic factors. RESULTS: In oxygen-induced retinopathy, flow cytometry revealed the numbers of CD4+ and CD8+ T cells were increased in blood, lymphoid organs, and retina throughout the development of neovascular retinopathy. Interestingly, the depletion of CD8+ T cells but not CD4+ T cells reduced retinal neovascularization and vascular leakage. Using reporter mice expressing gfp (green fluorescence protein) in CD8+ T cells, these cells were localized near neovascular tufts in the retina, confirming that CD8+ T cells contribute to the disease. Furthermore, the adoptive transfer of CD8+ T cells deficient in TNF (tumor necrosis factor), IFNγ (interferon gamma), Prf (perforin), or GzmA/B (granzymes A/B) into immunocompetent Rag1-/- mice revealed that CD8+ T cells mediate retinal vascular disease via these factors, with TNF influencing all aspects of vascular pathology. The pathway by which CD8+ T cells migrate into the retina was identified as CXCR3 (C-X-C motif chemokine receptor 3) with the CXCR3 blockade reducing the number of CD8+ T cells within the retina and retinal vascular disease. CONCLUSIONS: We discovered that CXCR3 is central to the migration of CD8+ T cells into the retina as the CXCR3 blockade reduced the number of CD8+ T cells within the retina and vasculopathy. This research identified an unappreciated role for CD8+ T cells in retinal inflammation and vascular disease. Reducing CD8+ T cells via their inflammatory and recruitment pathways is a potential treatment for neovascular retinopathies.
Assuntos
Doenças Retinianas , Doenças Vasculares , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Neovascularização Patológica , Retina/metabolismo , Doenças Retinianas/metabolismo , Interferon gama/metabolismo , Doenças Vasculares/patologia , Camundongos Endogâmicos C57BLRESUMO
While Salmonella enterica is seen as an archetypal facultative intracellular bacterial pathogen where protection is mediated by CD4+ T cells, identifying circulating protective cells has proved very difficult, inhibiting steps to identify key antigen specificities. Exploiting a mouse model of vaccination, we show that the spleens of C57BL/6 mice vaccinated with live-attenuated Salmonella serovar Typhimurium (S. Typhimurium) strains carried a pool of IFN-γ+ CD4+ T cells that could adoptively transfer protection, but only transiently. Circulating Salmonella-reactive CD4+ T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4+ T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4+ T cells mediating immunity to Salmonella is limited to a brief window after which Salmonella-specific CD4+ T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica/imunologia , Fígado/imunologia , Salmonelose Animal/imunologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Salmonella typhimurium/imunologiaRESUMO
Following their activation and expansion in response to foreign threats, many T cells are retained in peripheral tissues without recirculating in the blood. These tissue-resident CD8+ memory T (TRM) cells patrol barrier surfaces and nonlymphoid organs, where their critical role in protecting against viral and bacterial infections is well established. Recent evidence suggests that TRM cells also play a vital part in preventing the development and spread of solid tumors. Here, we discuss the emerging role of TRM cells in anticancer immunity. We highlight defining features of tumor-localizing TRM cells, examine the mechanisms through which they have recently been shown to suppress cancer growth, and explore their potential as future targets of cancer immunotherapy.
Assuntos
Memória Imunológica , Vigilância Imunológica , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Biomarcadores , Suscetibilidade a Doenças , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/patologia , Neoplasias/patologia , Neoplasias/terapia , Subpopulações de Linfócitos T/patologia , Microambiente Tumoral/imunologiaRESUMO
A large proportion of memory T cells disseminated throughout the body are non-recirculating cells whose maintenance and function is regulated by tissue-specific environmental cues. These sessile cells are referred to as tissue-resident memory T (TRM ) cells and similar populations of non-recirculating cells also exist among unconventional T cells and innate lymphocyte cells. The pool of TRM cells is highly diverse with respect to anatomical positioning, phenotype, molecular regulation and effector function. Nevertheless, certain transcriptional programs are shared and appear as important unifying features for the overall population of TRM cells and tissue-resident lymphocytes. It is now widely appreciated that TRM cells are a critical component of our immune defense by acting as peripheral sentinels capable of rapidly mobilizing protective tissue immunity upon pathogen recognition. This function is of particular importance in anatomical sites that are not effectively surveilled by blood-borne memory T cells in absence of inflammation, such as neuronal tissues or epithelial compartments in skin and mucosae. Focusing on the well-characterized subtype of CD8+ CD69+ CD103+ TRM cells, we will review current concepts on the generation, persistence and function of TRM cells and will summarize commonly used tools to study these cells. Furthermore, we will discuss accumulating data that emphasize localized TRM responses as an important determinant of tissue homeostasis and immune defense in the context of microbiota-immune interactions, persistent infections and cancer surveillance.
Assuntos
Homeostase , Memória Imunológica , Vigilância Imunológica , Infecções/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Biomarcadores , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Vigilância Imunológica/genética , Infecções/genética , Contagem de Linfócitos , Camundongos , Microbiota/imunologia , Modelos Biológicos , Neoplasias/genética , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Fenótipo , Subpopulações de Linfócitos T/metabolismo , TranscriptomaRESUMO
A recent study by Oliveira et al. provides, in unprecedented detail, novel insights into the relationship between tumorreactivity and functional states of CD8 T cells in metastatic melanoma.
Assuntos
Linfócitos T CD8-Positivos , Melanoma , Humanos , Proteínas de NeoplasiasRESUMO
Regulatory T cells (Tregs) play a critical role in immune regulation and peripheral tolerance. While different types of Tregs have been identified in both mice and humans, much of our understanding about how these cells maintain immune homeostasis is derived from animal models. In this study, we examined two distinct human lymphoid organs to understand how repeated exposure to infections at the mucosal surface influences the phenotype and tissue localization of Tregs. We show that while Tregs in both tonsils and spleen express a tissue-resident phenotype, they accumulate in greater numbers in tonsils. Tonsillar-resident Tregs exhibit a highly suppressive phenotype with significantly increased expression of CD39, ICOS and CTLA-4 compared with their counterparts in circulation or in the spleen. Functionally, resident Tregs are able effectively to suppress T cell proliferation. We further demonstrate that tonsillar-resident Tregs share key features of T follicular helper cells. Spatial analysis reveals that the vast majority of resident Tregs are localized at the border of the T-zone and B cell follicle, as well as within the lymphocyte pockets enriched with resident memory T cells. Together our findings suggest that resident Tregs are strategically co-localized to maintain immune homeostasis at sites of recurrent inflammation.