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OBJECTIVES: Patients with systemic lupus erythematosus (SLE) display heightened immune activation and elevated IgG autoantibody levels, indicating compromised regulatory T cell (Tregs) function. Our recent findings pinpoint CD8+ Tregs as crucial regulators within secondary lymphoid organs, operating in a NOX2-dependent mechanism. However, the specific involvement of CD8+ Tregs in SLE pathogenesis and the mechanisms underlying their role remain uncertain. METHODS: SLE and healthy individuals were enlisted to assess the quantity and efficacy of Tregs. CD8+CD45RA+CCR7+ Tregs were generated ex vivo, and their suppressive capability was gauged by measuring pZAP70 levels in targeted T cells. Notch1 activity was evaluated by examining activated Notch1 and HES1, with manipulation of Notch1 accomplished with Notch inhibitor DAPT, Notch1 shRNA, and Notch1-ICD. To create humanized SLE chimeras, immune-deficient NSG mice were engrafted with PBMCs from SLE patients. RESULTS: We observed a reduced frequency and impaired functionality of CD8+ Tregs in SLE patients. There was a downregulation of NOX2 in CD8+ Tregs from SLE patients, leading to a dysfunction. Mechanistically, the reduction of NOX2 in SLE CD8+ Tregs occurred at a post-translational level rather than at the transcriptional level. SLE CD8+ Tregs exhibited heightened Notch1 activity, resulting in increased expression of STUB1, an E3 ubiquitin ligase that binds to NOX2 and facilitates its ubiquitination. Consequently, restoring NOX2 levels and inhibiting Notch1 activity could alleviate the severity of the disease in humanized SLE chimeras. CONCLUSION: Notch1 is the cell-intrinsic mechanism underlying NOX2 deficiency and CD8+ Treg dysfunction, serving as a therapeutic target for clinical management of SLE.
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Liver-directed AAV gene therapy represents a unique treatment modality for a host of diseases. This is due, in part, to the induction of tolerance to transgene products. Despite the plethora of recognized regulatory cells in the body, there is currently a lack of literature supporting the induction of non-CD4+ regulatory cells following hepatic AAV gene transfer. In this work, we show that CD8+ regulatory T cells are up-regulated in PBMCs of mice following capsid only and therapeutic transgene AAV administration. Further, we demonstrate that hepatic AAV gene transfer results in a significant increase in CD8+ regulatory T cells following experimental autoimmune encephalomyelitis induction. Notably, this response occurred only in therapeutic vector treated animals, not capsid only controls. Understanding the role these cells play in treatment efficacy will result in the development of improved AAV vectors that take advantage of the full gamut of regulatory cells within the body.
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Técnicas de Transferencia de Gen , Linfocitos T Reguladores , Ratones , Animales , Regulación hacia Arriba , Dependovirus/genética , Hígado , Proteínas de la Cápside , Terapia Genética , Linfocitos T CD8-positivos , Vectores Genéticos/genéticaRESUMEN
Introduction: Immunosuppressive therapy prevents graft rejection but increases the risk of non-melanoma skin cancer (NMSC), especially in elderly kidney transplant recipients (KTR). Methods: In this study, we separately investigated the differentiation of CD8+ regulatory T cells (Tregs) and responder T cells (Tresps) between healthy KTR without NMSC, KTR developing de-novo NMSC within two years after the enrolment, and KTR with NMSC at the time of enrolment. Antigen-unexperienced CCR7+CD45RA+CD31+ recent thymic emigrant (RTE) cells differentiate via CD45RA-CD31+ memory (CD31+ memory) cells, via resting mature naïve (MN) cells or via direct proliferation into CD45RA-CD31- memory (CD31- memory) cells, consisting of both CCR7+CD45RA- central memory (CM) and CCR7-CD45RA- effector memory (EM) cells. Results: We found that both RTE Treg and Tresp differentiation via CD31+ memory Tregs/Tresps was age-independently increased in KTR, who developed de novo NMSC during the follow-up period, causing abundant CM Treg/Tresp production, which may be crucial for cancer immunity. These changes favored a strongly increased CD8+ Treg/Tresp ratio, suggesting this ratio as a reliable marker for de-novo NMSC development in KTR. However, with age, this differentiation was replaced by increased conversion of resting MN Tregs/Tresps into CM Tregs/Tresps, which exhausted for Tresps but not for Tregs. In KTR with already existing NMSC at enrolment, differentiation was maintained via conversion and proliferation of resting MN Tregs/Tresps, which however increasingly exhausted with age, especially for Tresps. This resulted in a strong accumulation of terminally differentiated effector memory (TEMRA) Tresps in elderly individuals. Patients with NMSC recurrence showed increased proliferation of resting MN Tregs/Tresps into EM Tregs/Tresps, which tended to exhaust more rapidly, particularly for Tresps, than in patients without NMSC recurrence. Discussion: In conclusion, we provide evidence that immunosuppressive therapy inhibits differentiation of CD8+ Tregs more than that of CD8+ Tresps, resulting in an exhausted Tresp profile, thus providing a possible therapeutic approach to improve poor cancer immunity in elderly KTR.
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Trasplante de Riñón , Neoplasias Cutáneas , Humanos , Anciano , Subgrupos de Linfocitos T , Trasplante de Riñón/efectos adversos , Receptores CCR7 , Diferenciación Celular , Linfocitos T CD8-positivosRESUMEN
Cancer immunotherapy is a powerful tool for inducing antigen-specific antitumor cytotoxic T lymphocytes (CTLs). Next-generation strategies may include vaccination against overexpressed oncogenic tumor-self antigens. Previously, we reported vaccination against the oncogenic tumor-self antigen D52 (D52) was effective in preventing tumor growth. We recently reported that D52-vaccinated IL-10-deficient mice generated a significant memory response against tumor recurrence compared to wild-type mice and that vaccine-induced CD8+ IL-10+ T cells may possess regulatory function. Herein, we extended these studies by testing the hypothesis that D52-vaccine-elicited CD8+ IL-10+ T cells represent a distinct T cell population with a regulatory phenotype. C57Black/6J mice deficient in IL-10 or IFN-γ were vaccinated with the murine orthologue of D52; vaccination of wild-type (wt) mice served as a control for comparison. T cells were isolated from all three groups of vaccinated mice, and RNA was extracted from purified CD8+ T cells for deep sequencing and expression analysis. Chemokine receptor 8 (CCR8) and inducible co-stimulator (ICOS) were overexpressed in CD8+ T cells that produced IL-10 but not IFN-γ. These surface markers are associated with IL-10 producing CD4+ T regulatory cells thus supporting the possibility that CD8+ IL-10+ T cells elicited by D52 vaccination represent a unique regulatory T cell subset. The current phenotypic analyses of D52 vaccine elicited CD8+ T cells strengthen our premise that CD8+ IL-10+ T cells elicited by D52 tumor-self protein vaccination likely contribute to the suppression of memory CTL responses and inhibition of durable tumor immunity.
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Vacunas contra el Cáncer , Neoplasias , Ratones , Animales , Interleucina-10 , Autoantígenos/metabolismo , Linfocitos T CD8-positivos , Linfocitos T CD4-Positivos , Antígenos de Neoplasias/genética , Vacunación , Neoplasias/metabolismoRESUMEN
Previous studies have demonstrated the regulatory functions of Ly49+CD8+ T cells toward self-reactive CD4+ T cells in mice. Recently, we found KIR+CD8+ T cells are the equivalent of mouse Ly49+CD8+ T cells in humans. They are increased in patients with autoimmune or infectious diseases as a negative feedback mechanism to suppress the arising pathogenic cells and maintain peripheral tolerance. Here, we describe the methods on how we characterize the KIR+CD8+ T cells from different diseases using single-cell RNA and TCR sequencing.
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ARN Citoplasmático Pequeño , Linfocitos T Reguladores , Animales , Linfocitos T CD8-positivos , Humanos , Ratones , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Análisis de la Célula IndividualRESUMEN
Objectives: Besides CD4 regulatory T-cells (Tregs), immunosuppressor FoxP3+ CD8 T-cells are emerging as an important subset of Tregs, which contribute to immune dysfunction and disease progression in HIV infection. However, FoxP3+ CD8 T-cell dynamics in acute HIV infection and following early antiretroviral therapy (ART) initiation remain understudied. Methods: Subsets of FoxP3+ CD8 T-cells were characterized both prospectively and cross-sectionally in PBMCs from untreated acute (n=26) and chronic (n=10) HIV-infected individuals, early ART-treated in acute infection (n=10, median of ART initiation: 5.5 months post-infection), ART-treated in chronic infection (n=10), elite controllers (n=18), and HIV-uninfected controls (n=21). Results: Acute and chronic infection were associated with increased total, effector memory, and terminally differentiated FoxP3+ CD8 T-cells, while early ART normalized only the frequencies of total FoxP3+ CD8 T-cells. We observed an increase in FoxP3+ CD8 T-cell immune activation (HLADR+/CD38+), senescence (CD57+/CD28-), and PD-1 expression during acute and chronic infection, which were not normalized by early ART. FoxP3+ CD8 T-cells in untreated participants expressed higher levels of immunosuppressive LAP(TGF-ß1) and CD39 than uninfected controls, whereas early ART did not affect their expression. The expression of gut-homing markers CCR9 and Integrin-ß7 by total FoxP3+ CD8 T-cells and CD39+ and LAP(TGF-ß1)+ FoxP3+ CD8 T-cells increased in untreated individuals and remained higher than in uninfected controls despite early ART. Elite controllers share most of the FoxP3+ CD8 T-cell characteristics in uninfected individuals. Conclusions: Although early ART normalized total FoxP3+ CD8 T-cells frequencies, it did not affect the persistent elevation of the gut-homing potential of CD39+ and LAP(TGF-ß1)+ FoxP3+ CD8 T-cell, which may contribute to immune dysfunction.
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Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéutico , Linfocitos T CD8-positivos , Factores de Transcripción Forkhead/metabolismo , Humanos , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Chronic kidney failure (KF) provokes the development of immune senescent CD8+ cytotoxic T cells, affecting the occurrence of graft rejection, viral infections, and malignancies after kidney transplantation. In this study, we analyzed the impact of KF, subsequent dialysis treatment, and kidney transplantation on the differentiation of CD8+CD31+CD45RA+CCR7+ recent thymic emigrant (CCR7+ RTE) Tregs/Tresps into CD8+CD31-CD45RA- memory (CD31- memory) Tregs/Tresps and its effect on the release of cytokines, Fas receptor, Fas ligand as well as cytotoxic mediators by naïve, central memory (CM), effector memory (EM), and terminally differentiated effector memory (TEMRA) Tresps. We found that normal age-dependent differentiation of CD8+ Tregs/Tresps generally differs in the way that TEMRA cells only arise in Tresps. Compared to healthy controls, KF patients revealed an age-independently decreased frequency of CCR7+ RTE Tregs/Tresps, but increased frequencies of CCR7+ MN Tregs/Tresps and CD31- memory Tregs/Tresps, suggesting an increased differentiation via CD31+CD45RA- memory (CD31+ memory) Tregs/Tresps into CD31- memory Tregs/Tresps. Intensified differentiation via CD31+ memory Tresps increased the emergence of apoptosis-resistant CM Tresps with strong Fas ligand-mediated cytotoxicity. CCR7+ RTE Tresp proliferation generated TEMRA Tresps, secreting high levels of cytotoxic mediators. In dialysis and transplant patients, CD31+ TEMRA Tregs/Tresps accumulated, proposing an impaired CCR7+ RTE Treg/Tresp differentiation via CD31+ memory Tregs/Tresps into CD31- memory Tregs/Tresps. Increased percentages of CD31- TEMRA Tresps, but not of CD31- TEMRA Tregs, were observed in all patient groups, indicating impaired proliferation of CCR7+ RTE Tresps, but not of CCR7+ RTE Tregs, into CD31- memory Tregs/Tresps. In transplant patients, CCR7+ RTE Tregs accumulated, while frequencies of CCR7+ RTE Tresps were decreased, suggesting that the immunosuppressive therapy only prevented excessive CCR7+ RTE Treg differentiation but not that of CCR7+ RTE Tresps. Presumably, this caused the accumulation of TEMRA Tresps with decreased release of cytotoxic mediators, such as perforin. In conclusion, we propose that chronic KF affects both the differentiation of CD8+ Tregs and CD8+ Tresps. However, the immunosuppressive therapy after transplantation may successfully prevent excessive Treg differentiation, but not as suffciently that of Tresps. Therefore, the risk for graft rejection may be reduced, while the susceptibility for infections and malignancies may be increased in these patients.
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Fallo Renal Crónico , Trasplante de Riñón , Linfocitos T CD8-positivos , Humanos , Memoria Inmunológica , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Antígenos Comunes de Leucocito , Receptores CCR7 , Subgrupos de Linfocitos T , Linfocitos T ReguladoresRESUMEN
CD8 T cells are key players in the clearance of human immunodeficiency virus (HIV)-infected cells, such that CD8 T-cell dysfunction contributes to viral persistence despite antiretroviral (ARV) therapy. Mesenteric lymph nodes (MLNs) are major sites of gut mucosal immunity. While different CD8 T cell subsets such as CD8 alpha-alpha (CD8αα), CD8 alpha-beta (CD8αß), CD8 regulatory T cells (Treg), and mucosa-associated invariant T cells (MAIT) are present in the gut and exhibit distinct functions, their dynamics remain poorly understood due to the lack of accessibility to these tissues in humans. We thus assessed CD8 T cells in MLNs versus peripheral blood in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) following early ARV therapy initiation. SIV infection was associated with an increase over time of both CD8αß and CD8αα T cells in the blood and MLNs, whereas early ARV initiation significantly decreased the frequencies of CD8αα but not CD8αß T cells in MLNs. A significant decrease in the expression of chemokine receptors CCR6 and CXCR3 by CD8 T cells, which are essential for T-cell trafficking to the inflammatory sites, was observed in chronically SIV-infected RMs. Surprisingly, while MAIT cells are increased in ARV-treated RMs, their frequencies in MLN are extremely low and were not impacted by ARV. The acute infection resulted in an early CD39+FoxP3+ CD8 Tregs increase in both compartments, which was normalized after early ARV. Frequencies of CD8 Treg cells were positively correlated with frequencies of CD4 Tregs and accordingly negatively correlated with the Th17/Treg ratio in the blood but not in MLNs. Overall, our results underscore the difference in CD8 T-cell subset dynamics in the blood and MLNs. IMPORTANCE Changes in CD8 T-cell subsets during acute SIV/HIV infections and following early ARV initiation in gut lymphoid tissues are poorly understood. Using an acute SIV infection model in rhesus macaques, we assessed the impact of early ARV, initiated 4 days postinfection, on relative proportions of CD8 T-cell subsets in MLNs compared to blood. We found that acute SIV infection and early ARV initiation differentially affect the distribution of effector CD8 T cells, CD8 MAIT cells, and CD8 Tregs in MLNs compared to blood. Overall, early ARV initiation maintains the frequency of effector CD8 T cells while reducing immunosuppressive CD39+ CD8 Tregs. Our study provides deeper insight into the dynamics of the CD8 T-cell compartment in gut mucosal immune surveillance during acute SIV infection and following early ARV initiation.
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Linfocitos T CD8-positivos , Ganglios Linfáticos , Síndrome de Inmunodeficiencia Adquirida del Simio , Linfocitos T Reguladores , Animales , Antirretrovirales/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Infecciones por VIH/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: Circulating CD8+ T-cells expressing the C-X-C chemokine receptor type 5 (CXCR5) (CD8+CXCR5+T), a recently identified follicular cytotoxic T cell subset, are involved in antiviral immunity and autoimmunity, but their abundance and role in the pathogenesis of primary Sjögren syndrome (pSS) are unknown. METHODS: Circulating CD8+CXCR5+T cell and CD8+ regulatory T cells (CD8+Treg) were evaluated in 49 pSS patients (19 patients with pulmonary involvement) and 24 age- and sex-matched healthy controls (HCs) by flow cytometry. Orthogonal partial least squares discriminant analysis (OPLS-DA) was performed, and receiver operating characteristic curves (ROC) were generated to identify characteristic cell subsets. Spearman's correlation analysis was conducted to examine the relationships between CD8+ T cell subsets and clinical features. RESULTS: The proportions and numbers of CD8+CXCR5+, CD8 + CXCR5+ programmed death 1-positive (PD-1+), and CD8+CXCR5-PD-1+T cells were significantly higher, whereas those of CD8+Treg were markedly lower, in pSS patients than HCs. The CD8+CXCR5+PD-1+T cell to CD8+Treg ratio had the greatest discriminatory power for pSS and HCs according to OPLS-DA and ROC analyses. The increased numbers of CD8+CXCR5+T cells and CD8+CXCR5+PD-1+T cells were strongly associated with those of CD4+CXCR5+T and B cells. The proportions and numbers of CD8+CXCR5+PD-1+T cells were increased in pSS patients with lung involvement. CONCLUSIONS: We identified a new CD8+CXCR5+PD-1+T subset, which was increased in abundance in pSS patients, particularly those with lung involvement, compared with HCs. Also, the CD8+CXCR5+PD-1+T to CD8+Treg ratio may be useful for identifying pSS. Our findings suggest that targeting follicular CD8+T cell subsets has therapeutic potential for pSS. Key Points ⢠CD8+CXCR5+ T cells were expanded in the circulation of patients with pSS. ⢠Reduced numbers CD8+Treg cells in pSS patients. ⢠Increased CD8+CXCR5+PD-1+T cells in pSS patients with pulmonary involvement.
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Síndrome de Sjögren , Linfocitos T CD8-positivos , Humanos , Receptor de Muerte Celular Programada 1 , Receptores CXCR5/análisis , Síndrome de Sjögren/patología , Subgrupos de Linfocitos T , Linfocitos T ReguladoresRESUMEN
Colorectal cancer (CRC) represents the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Although immunotherapy has taken center stage in mainstream oncology, it has shown limited clinical efficacy in CRC, generating an urgent need for discovery of new biomarkers and potential therapeutic targets. Galectin-1 (Gal-1), an endogenous glycan-binding protein, induces tolerogenic programs and contributes to tumor cell evasion of immune responses. Here, we investigated the relevance of Gal-1 in CRC and explored its modulatory activity within the CD8+ regulatory T cell (Treg) compartment. Mice lacking Gal-1 (Lgals1-/- ) developed a lower number of tumors and showed a decreased frequency of a particular population of CD8+CD122+PD-1+ Tregs in the azoxymethane-dextran sodium sulfate model of colitis-associated CRC. Moreover, silencing of tumor-derived Gal-1 in the syngeneic CT26 CRC model resulted in reduced number and attenuated immunosuppressive capacity of CD8+CD122+PD-1+ Tregs, leading to slower tumor growth. Moreover, stromal Gal-1 also influenced the fitness of CD8+ Tregs, highlighting the contribution of both tumor and stromal-derived Gal-1 to this immunoregulatory effect. Finally, bioinformatic analysis of a colorectal adenocarcinoma from The Cancer Genome Atlas dataset revealed a particular signature characterized by high CD8+ Treg score and elevated Gal-1 expression, which delineates poor prognosis in human CRC. Our findings identify CD8+CD122+PD-1+ Tregs as a target of the immunoregulatory activity of Gal-1, suggesting a potential immunotherapeutic strategy for the treatment of CRC.
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Adenocarcinoma/genética , Linfocitos T CD8-positivos/inmunología , Colitis/genética , Neoplasias Colorrectales/genética , Galectina 1/genética , Linfocitos T Reguladores/inmunología , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Animales , Atlas como Asunto , Azoximetano/administración & dosificación , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Colitis/inducido químicamente , Colitis/inmunología , Colitis/mortalidad , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Biología Computacional , Sulfato de Dextran/administración & dosificación , Modelos Animales de Enfermedad , Galectina 1/deficiencia , Galectina 1/inmunología , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidad beta del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/inmunología , Ratones , Ratones Noqueados , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Análisis de Supervivencia , Linfocitos T Reguladores/patología , Carga TumoralRESUMEN
BACKGROUND: CD8+ regulatory T cells (CD8+ Tregs) are relatively recently described T cell subsets that have been shown to regulate various T cell responses and appear to play a role in autoimmunity. However, their effects on B cells have not been explored. OBJECTIVES: In this investigation we examine the effect of CD8+ Tregs on various subsets of peripheral B cells include naïve B cells, transitional B cells, marginal zone B cells, IgM memory B cells, class switched memory B cells, and plasmablasts, and on the expression of B cell-activating factor receptor (BAFF-R). METHODS: CD8+ T cells were first purified and then activated with anti-CD3/CD28 beads to generate CD8+ Tregs. Purified CD19+ B cells were cultured alone or with sorted CD8+ Tregs (CD8+CD183+CCR7+CD45RA-) and activated with anti-CD40 monoclonal antibody and CpG. B cell subsets and the expression of BAFF-R on naïve and memory B cells were analyzed using various monoclonal antibodies and corresponding control isotypes. Ten thousand cells were acquired and analyzed by FACSCalibur using the FlowJo software. RESULTS: CD8+ Tregs selectively and significantly suppressed plasmablasts without any significant effect on other B cell subsets or on the expression of BAFF-R. CONCLUSION: CD8+ Tregs may play a role in autoimmunity by regulating antibody production via suppression of plasmablasts.
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Autoinmunidad/inmunología , Subgrupos de Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T Reguladores/inmunología , Células Cultivadas , HumanosRESUMEN
Extracorporeal photochemotherapy (ECP) that takes advantage of the immunomodulatory effects of UV light has been extensively used for many years for the treatment of several T cell-mediated diseases, including graft-versus-host disease (GvHD) and systemic scleroderma. Immune mechanisms that lead to the establishment of T cell tolerance in ECP-treated patients remain poorly known. In this study, we have tested the effect of UV/psoralen-treated BM-derived dendritic cells, referred to as ECP-BMDCs on the outcome of an antigen-specific T cell-mediated reaction, that is, contact hypersensitivity (CHS), which is mediated by CD8+ effector T cells (CD8+ Teff ). The intravenous (i.v.) injection of antigen-pulsed ECP-BMDCs in recipient C57BL/6 mice induced specific CD8+ T cells endowed with immunomodulatory properties (referred to as CD8+ TECP ), which prevented the priming of CD8+ Teff and the development of CHS, independently of conventional CD4+ regulatory T cells. CD8+ TECP mediated tolerance by inhibiting the migration and functions of skin DC and subsequently the priming of CD8+ Teff . CD8+ TECP displayed none of the phenotypes of the usual CD8+ T regulatory cells described so far. Our results reveal an underestimated participation of CD8+ T cells to ECP-induced immunomodulation that could explain the therapeutic effects of ECP in T cell-mediated diseases.
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Células Dendríticas/inmunología , Dermatitis por Contacto/terapia , Tolerancia Inmunológica , Inmunomodulación/efectos de la radiación , Linfocitos T Citotóxicos/efectos de la radiación , Linfocitos T Reguladores/efectos de la radiación , Alérgenos/administración & dosificación , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Células Dendríticas/citología , Células Dendríticas/trasplante , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/fisiopatología , Dinitrofluorobenceno/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Ficusina/administración & dosificación , Humanos , Ratones Endogámicos C57BL , Ratones Transgénicos , Fotoféresis/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Rayos UltravioletaRESUMEN
Development of cancer vaccines targeting tumor self-antigens is complex and challenging due to the difficulty of overcoming immune tolerance to self-proteins. Vaccination against tumor self-protein D52 (D52) has been successful, although complete protection appears impaired by immune regulation. Our previous studies suggest that vaccine elicited CD8 + T cells producing interleukin 10 (IL-10) may have a negative impact on tumor protection. Understanding the role CD8+ IL-10 + T cells play in the immune response following vaccination with D52 could result in a more potent vaccine. To address this, we vaccinated IL-10 deficient mice with the murine orthologue of D52; vaccination of wild type (wt) C57BL/6J served as a control for comparison. In separate experiments, D52 vaccinated wt mice were administered IL-10R-specific mAb to neutralize IL-10 function. Interestingly, we observed similar protection against primary tumor challenge in the experimental groups compared to the controls. However, individual IL-10 deficient mice that rejected the primary tumor challenge were re-challenged 140 days post-primary challenge to access vaccine durability and immunologic memory against tumor recurrence. Mice deficient in IL-10 demonstrated a memory response in which 100% of the mice were protected from secondary tumor challenge, while wt mice had diminished recall response (25%) against tumor recurrence. These results with analysis of vaccine-elicited CD8 + T cells for tumor-specific killing and regulatory cell marker expression, add further support to our premise that CD8+ IL-10 + T cells elicited by D52 tumor-self protein vaccine contribute to the suppression of a memory CTL responses and durable tumor immunity.
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Linfocitos T CD8-positivos , Vacunas contra el Cáncer/inmunología , Proteínas de Neoplasias/inmunología , Recurrencia Local de Neoplasia , Animales , Interleucina-10 , Ratones , Ratones Endogámicos C57BL , VacunaciónRESUMEN
Multiple sclerosis (MS) is a neuro-immunological demyelinating disease. From the immunological aspects, it is well accepted that T cells play a pivotal role in the etiology of the disease. T helper (Th) 1 and Th17 cells are thought to be the main pathogenic T cells in the pathogenesis of MS and are known as effector T cells. As the self-reactive T lymphocytes can escape clonal deletion in the thymus and subsequently are released into the periphery, there is an urgent need for peripheral tolerance, which is executed by the specialized regulatory T (Treg) cells. Interestingly, CD8+ regulatory T (Treg) cells have also been identified among lymphocyte subtypes. The peripheral CD8+ Treg cells frequency in MS subjects in comparison with healthy controls is the objective of the current study using the systematic review and meta-analysis. A systematic literature search was carried out using specialized biomedical databases of Pubmed, Pubmed Central, Medline, Google Scholar, Embase and SCOPUS databases without the beginning date restriction until January 2018 in English language. The results were as follows: OR 15.548 (95% confidence interval 1.954-123.742) using the random-effects model. The P value for test of significance of the total OR was examined by the z test and calculated as 0.010 (clearly considered as statistically significant). Based on our findings, the number of CD8+ Treg cells in the blood of MS subjects is significantly different as compared to healthy controls.
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Linfocitos T CD8-positivos/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/inmunología , Femenino , Humanos , MasculinoRESUMEN
Periodontitis is a dysbiotic bacteria-mediated disease characterized by periodontal inflammations and alveolar bone damage. Its mechanisms were complicated, involving an inflammation-mediated bone destruction. We sought to determine roles and rules that CD8+ regulatory T cells (CD8+ Tregs) affect alveolar bone homeostasis during periodontitis. Presence of CD8+ Tregs in the gingiva, cervical lymph nodes (CLNs), and spleens of healthy or periodontitis animals was analyzed. CD8+ regulatory T cells from periodontitis animals were sorted by magnetic-activated cell sorting and fluorescent-activated cell sorting technique, subsequently injected into recipient animals to set adoptive transfer model. We induced experimental periodontitis on transfer models and equal number healthy animals. Four weeks later, their alveolar bone loss and osteoclast coverage length were measured. We also detected CD8+ Tregs, CD4+ T cell, CD4+ Tregs, Th17 cell, and IL-1ß, IL-6, IL-10, IL-17A, RANKL, TGF-ß expression in the gingiva, CLNs, and spleen to illustrate possible working mechanism of CD8+ regulatory T cells. Periodontitis does not induce significant change on proportion or amount of CD8+ Tregs. Adoptive transfer of CD8+ Tregs reduces alveolar bone destruction and osteoclast formation. In addition, experimental periodontitis increases percentage of Th17 cells and decreases CD4+ Tregs in the gingiva and CLNs. More IL-1ß, IL-6, IL-17A, and RANKL, and less IL-10 and TGF-ß are also detected in the gingiva and CLNs from animals with periodontitis than the one from healthy animals. Adoptive transfer of CD8+ regulatory T cells remedies all above pathological change effectively. We did not find any significant difference in spleen, regardless group and detected items. Outcomes of present study clarify function that CD8+ regulatory T cells affect alveolar bone homeostasis, and disclose its possible working mechanisms. CD8+ regulatory T cells protect alveolar bone via reducing osteoclastogenesis and modulating local immune response.
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Traslado Adoptivo/métodos , Proceso Alveolar/fisiología , Linfocitos T CD8-positivos/trasplante , Factores de Transcripción Forkhead , Homeostasis , Periodontitis/terapia , Pérdida de Hueso Alveolar/terapia , Animales , Encía , Ganglios Linfáticos , Osteogénesis , Bazo , Células Th17/inmunologíaRESUMEN
Various subgroups of CD8+ T lymphocytes do not only demonstrate cytotoxic effects, but also serve important regulatory roles in the body's immune response. In particular, CD8+ regulatory T cells (CD8+ Tregs), which possess important immunosuppressive functions, are able to effectively block the overreacting immune response and maintain the body's immune homeostasis. In recent years, studies have identified a small set of special CD8+ Tregs that can recognize major histocompatibility complex class Ib molecules, more specifically Qa-1 in mice and HLA-E in humans, and target the self-reactive CD4+ T ce lls. These findings have generated broad implications in the scientific community and attracted general interest to CD8+ Tregs. The present study reviews the recent research progress on CD8+ Tregs, including their origin, functional classification, molecular markers and underlying mechanisms of action.
RESUMEN
Tumor necrosis factor (TNF) is a pleiotropic cytokine that has both pro-inflammatory and anti-inflammatory functions. The biological functions of TNF are mediated by two receptors, TNF receptor type I (TNFR1) and TNF receptor type II (TNFR2). TNFR1 is expressed universally on almost all cell types and has been extensively studied, whereas TNFR2 is mainly restricted to immune cells and some tumor cells and its role is far from clarified. Studies have shown that TNFR2 mediates the stimulatory activity of TNF on CD4+Foxp3+ regulatory T cells (Tregs) and CD8+Foxp3+ Tregs, and is involved in the phenotypic stability, proliferation, activation, and suppressive activity of Tregs. TNFR2 can also be expressed on CD8+ effector T cells (Teffs), which delivers an activation signal and cytotoxic ability to CD8+ Teffs during the early immune response, as well as an apoptosis signal to terminate the immune response. TNFR2-induced abolition of TNF receptor-associated factor 2 (TRAF2) degradation may play an important role in these processes. Consequently, due to the distribution of TNFR2 and its pleiotropic effects, TNFR2 appears to be critical to keeping the balance between Tregs and Teffs, and may be an efficient therapeutic target for tumor and autoimmune diseases. In this review, we summarize the biological functions of TNFR2 expressed on CD8+Foxp3+ Tregs and CD8+ Teffs, and highlight how TNF uses TNFR2 to coordinate the complex events that ultimately lead to efficient CD8+ T cell-mediated immune responses.
Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Apoptosis/inmunología , Biomarcadores , Linfocitos T CD8-positivos/inmunología , Citotoxicidad Inmunológica , Regulación de la Expresión Génica , Humanos , Inmunidad , Memoria Inmunológica , Activación de Linfocitos/inmunología , Fenotipo , Unión Proteica , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
In vitro observations suggest a role for the mouse heterochromatin protein 1γ (HP-1γ) in the immune system. However, it has not been shown if and how HP-1γ contributes to immunity in vivo. Here we show that in mice, HP-1γ positively regulates the germinal center reaction and high-affinity antibody response to thymus (T)-dependent antigens by limiting the size of CD8(+) regulatory T-cell (Treg) compartment without affecting progenitor B- or T-cell-development. Moreover, HP-1γ does not control cell proliferation or class switch recombination. Haploinsufficiency of cbx-3 (gene encoding HP-1γ) is sufficient to expand the CD8(+) Treg population and impair the immune response in mice despite the presence of wild-type HP-1α and HP-1ß. This is the first in vivo evidence demonstrating the non-redundant role of HP-1γ in immunity.
RESUMEN
We report that polyclonal CD8regs generated in one week ex-vivo with anti-CD3/28 beads and cytokines rapidly developed suppressive activity in vitro sustained by TGF-ß. In immunodeficient mice, these CD8regs demonstrated a markedly protective, IL-10 dependent activity against a xeno-GVHD. They expressed IL-2Rα/ß, Foxp3, TNFR2, and the negative co-stimulatory receptors CTLA-4, PD-1, PD-L1 and Tim-3. Suppressive activity in vitro correlated better with TNFR2 and PD-L1 than Foxp3. Blocking studies suggested that TNF enhanced PD-L1 expression and the suppressive activity of the CD8regs generated. Unlike other polyclonal CD4 and CD8 Tregs, these CD8regs preferentially targeted allogeneic T cells, but they lacked cytotoxic activity against them even after sensitization. Unlike CD4regs, these CD8regs could produce IL-2 and proliferate while inhibiting target cells. If these CD8regs can persist in foreign hosts without impairing immune surveillance, they could serve as a practical remission-inducing product for the treatment of autoimmune diseases, graft-versus-host disease, and allograft rejection.