RESUMEN
Vγ9Vδ2 T cells respond in a TCR-dependent fashion to both microbial and host-derived pyrophosphate compounds (phosphoantigens, or P-Ag). Butyrophilin-3A1 (BTN3A1), a protein structurally related to the B7 family of costimulatory molecules, is necessary but insufficient for this process. We performed radiation hybrid screens to uncover direct TCR ligands and cofactors that potentiate BTN3A1's P-Ag sensing function. These experiments identified butyrophilin-2A1 (BTN2A1) as essential to Vγ9Vδ2 T cell recognition. BTN2A1 synergised with BTN3A1 in sensitizing P-Ag-exposed cells for Vγ9Vδ2 TCR-mediated responses. Surface plasmon resonance experiments established Vγ9Vδ2 TCRs used germline-encoded Vγ9 regions to directly bind the BTN2A1 CFG-IgV domain surface. Notably, somatically recombined CDR3 loops implicated in P-Ag recognition were uninvolved. Immunoprecipitations demonstrated close cell-surface BTN2A1-BTN3A1 association independent of P-Ag stimulation. Thus, BTN2A1 is a BTN3A1-linked co-factor critical to Vγ9Vδ2 TCR recognition. Furthermore, these results suggest a composite-ligand model of P-Ag sensing wherein the Vγ9Vδ2 TCR directly interacts with both BTN2A1 and an additional ligand recognized in a CDR3-dependent manner.
Asunto(s)
Antígenos/inmunología , Butirofilinas/inmunología , Células Germinativas/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Animales , Antígenos/metabolismo , Antígenos CD/química , Antígenos CD/inmunología , Antígenos CD/metabolismo , Butirofilinas/química , Butirofilinas/metabolismo , Células CHO , Cricetinae , Cricetulus , Células Germinativas/metabolismo , Células HEK293 , Humanos , Fosforilación , Unión Proteica , Multimerización de Proteína , Receptores de Antígenos de Linfocitos T gamma-delta/química , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/metabolismoRESUMEN
The activating natural killer (NK)-cell receptor KIR3DS1 has been linked to the outcome of various human diseases, including delayed progression of disease caused by human immunodeficiency virus type 1 (HIV-1), yet a ligand that would account for its biological effects has remained unknown. We screened 100 HLA class I proteins and found that KIR3DS1 bound to HLA-F, a result we confirmed biochemically and functionally. Primary human KIR3DS1(+) NK cells degranulated and produced antiviral cytokines after encountering HLA-F and inhibited HIV-1 replication in vitro. Activation of CD4(+) T cells triggered the transcription and surface expression of HLA-F mRNA and HLA-F protein, respectively, and induced binding of KIR3DS1. HIV-1 infection further increased the transcription of HLA-F mRNA but decreased the binding of KIR3DS1, indicative of a mechanism for evading recognition by KIR3DS1(+) NK cells. Thus, we have established HLA-F as a ligand of KIR3DS1 and have demonstrated cell-context-dependent expression of HLA-F that might explain the widespread influence of KIR3DS1 in human disease.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/fisiología , Antígenos de Histocompatibilidad Clase I/metabolismo , Células Asesinas Naturales/inmunología , Receptores KIR3DS1/metabolismo , Citocinas/metabolismo , Citotoxicidad Inmunológica , Progresión de la Enfermedad , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Evasión Inmune , Células Jurkat , Ligandos , Activación de Linfocitos , Cultivo Primario de Células , Receptores KIR3DS1/agonistas , Receptores KIR3DS1/genética , Latencia del Virus , Replicación ViralRESUMEN
The involvement of γδ TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. γδ T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of αß T cell deficient mice in order to analyze the memory potential of γδ T cells. As for CMV-specific αß T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ γδ TEM that principally localized in infected organ vasculature. Typifying T cell memory, γδ T cell expansion in organs and blood was higher after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection was prevented when masking γδ T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR δ chain repertoire composed of a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, long-term-primed γδ TCM cells, but not γδ TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. This better survival potential of TCM cells was confirmed by a detailed scRNASeq analysis of the two γδ T cell memory subsets which also revealed their similarity to classically adaptive αß CD8 T cells. Overall, our study uncovered memory properties of long-lived TCM γδ T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches.
Asunto(s)
Infecciones por Herpesviridae , Memoria Inmunológica , Células T de Memoria , Muromegalovirus , Receptores de Antígenos de Linfocitos T gamma-delta , Animales , Ratones , Muromegalovirus/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Infecciones por Herpesviridae/inmunología , Memoria Inmunológica/inmunología , Células T de Memoria/inmunología , Reinfección/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Citomegalovirus/inmunologíaRESUMEN
T cells bearing γδ T cell antigen receptors (TCRs) function in lymphoid stress surveillance. However, the contribution of γδ TCRs to such responses is unclear. Here we found that the TCR of a human V(γ)4V(δ)5 clone directly bound endothelial protein C receptor (EPCR), which allowed γδ T cells to recognize both endothelial cells targeted by cytomegalovirus and epithelial tumors. EPCR is a major histocompatibility complex-like molecule that binds lipids analogously to the antigen-presenting molecule CD1d. However, the V(γ)4V(δ)5 TCR bound EPCR independently of lipids, in an antibody-like way. Moreover, the recognition of target cells by γδ T cells required a multimolecular stress signature composed of EPCR and costimulatory ligand(s). Our results demonstrate how a γδ TCR mediates recognition of broadly stressed human cells by engaging a stress-regulated self antigen.
Asunto(s)
Antígenos CD/inmunología , Infecciones por Citomegalovirus/inmunología , Vigilancia Inmunológica/inmunología , Neoplasias Glandulares y Epiteliales/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Superficie Celular/inmunología , Estrés Fisiológico/inmunología , Antígenos CD/metabolismo , Citomegalovirus/inmunología , Receptor de Proteína C Endotelial , Humanos , Immunoblotting , Inmunoprecipitación , Unión Proteica , Receptores de Antígenos de Linfocitos T gamma-delta/química , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de Superficie Celular/metabolismo , Subgrupos de Linfocitos T/química , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T/química , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality in immunocompromised patients, namely solid organ and hematopoietic cell transplant recipients, and can induce congenital infection in neonates. There is currently an unmet need for new management and treatment strategies. Establishment of an anti-CMV immune response is critical in order to control CMV infection. The two main human T cells involved in HCMV-specific response are αß and non-Vγ9Vδ2 T cells that belong to γδ T cell compartment. CMV-induced non-Vγ9Vδ2 T cells harbor a specific clonal expansion and a phenotypic signature, and display effector functions against CMV. So far, only two main molecular mechanisms underlying CMV sensing have been identified. Non-Vγ9Vδ2 T cells can be activated either by stress-induced surface expression of the γδT cell receptor (TCR) ligand annexin A2, or by a multimolecular stress signature composed of the γδTCR ligand endothelial protein C receptor and co-stimulatory signals such as the ICAM-1-LFA-1 axis. All this basic knowledge can be harnessed to improve the clinical management of CMV infection in at-risk patients. In particular, non-Vγ9Vδ2 T cell monitoring could help better stratify the risk of infection and move forward a personalized medicine. Moreover, recent advances in cell therapy protocols open the way for a non-Vγ9Vδ2 T cell therapy in immunocompromised patients.
Asunto(s)
Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Infecciones por Citomegalovirus/terapia , Humanos , Huésped Inmunocomprometido , Receptores de Antígenos de Linfocitos T gamma-delta , Subgrupos de Linfocitos TRESUMEN
BACKGROUND: The reported association of mTOR-inhibitor (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in kidney transplant recipients (KTR) who are CMV seropositive (R+) remains unexplained. METHODS: The incidence of CMV infection and T-cell profile was compared between KTRs treated with mTORis and mycophenolic acid (MPA), and in vitro mTORi effects on T-cell phenotype and functions were analyzed. RESULTS: In KTRs who were R+ and treated with MPA, both αß and γδ T cells displayed a more dysfunctional phenotype (PD-1+, CD85j+) at day 0 of transplantation in the 16 KTRs with severe CMV infection, as compared with the 17 KTRs without or with spontaneously resolving CMV infection. In patients treated with mTORis (n=27), the proportion of PD-1+ and CD85j+ αß and γδ T cells decreased, when compared with patients treated with MPA (n=44), as did the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of late-differentiated and cytotoxic γδ T cells and IFNγ-producing and cytotoxic αß T cells. In vitro, mTORis increased proliferation, viability, and CMV-induced IFNγ production of T cells and decreased PD-1 and CD85j expression in T cells, which shifted the T cells to a more efficient EOMESlow Hobithigh profile. In γδ T cells, the mTORi effect was related to increased TCR signaling. CONCLUSION: Severe CMV replication is associated with a dysfunctional T-cell profile and mTORis improve T-cell fitness along with better control of CMV. A dysfunctional T-cell phenotype could serve as a new biomarker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Proportion of CMV Seropositive Kidney Transplant Recipients Who Will Develop a CMV Infection When Treated With an Immunosuppressive Regimen Including Everolimus and Reduced Dose of Cyclosporine Versus an Immunosuppressive Regimen With Mycophenolic Acid and Standard Dose of Cyclosporine A (EVERCMV), NCT02328963.
Asunto(s)
Infecciones por Citomegalovirus/prevención & control , Trasplante de Riñón/efectos adversos , Inhibidores mTOR/uso terapéutico , Subgrupos de Linfocitos T/efectos de los fármacos , Anciano , Antibacterianos/uso terapéutico , Antígenos CD/metabolismo , Técnicas de Cultivo de Célula , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/patología , Femenino , Humanos , Receptor Leucocitario Tipo Inmunoglobulina B1/metabolismo , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Receptor de Muerte Celular Programada 1/metabolismo , Subgrupos de Linfocitos T/metabolismoRESUMEN
Cytomegalovirus (CMV) persists as the most frequent opportunistic infection among solid organ transplant recipients. This multicenter trial aimed to test whether treatment with everolimus (EVR) could decrease the incidence of CMV DNAemia and disease. We randomized 186 CMV seropositive kidney transplant recipients in a 1:1 ratio to receive EVR or mycophenolic acid (MPA) in association with basiliximab, cyclosporin, and steroids and 87 in each group were analyzed. No universal prophylaxis was administered to either group. The composite primary endpoint was the presence of CMV DNAemia, CMV treatment, graft loss, death, and discontinuation of the study at 6 months posttransplant. In the modified intent-to-treat analysis, 42 (48.3%) and 70 (80.5%) patients in the EVR and MPA groups reached the primary endpoint (OR = 0.21, 95% CI: 0.11-0.43, p < .0001). Fewer patients of the EVR group received treatment for CMV (21.8% vs. 47.1%, p = .0007). EVR was discontinued in 31 (35.6%) patients. Among the 56 patients with ongoing EVR treatment, only 7.4% received treatment for CMV. In conclusion, EVR prevents CMV DNAemia requiring treatment in seropositive recipients as long as it is tolerated and maintained.
Asunto(s)
Infecciones por Citomegalovirus , Trasplante de Riñón , Antivirales/uso terapéutico , Citomegalovirus , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/etiología , Everolimus/uso terapéutico , Humanos , Inmunosupresores/efectos adversos , Incidencia , Trasplante de Riñón/efectos adversos , Ácido Micofenólico/uso terapéutico , Receptores de TrasplantesRESUMEN
γδ T lymphocytes represent â¼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In t-distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV+ and CMV- donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions.
Asunto(s)
Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Secuencia de Bases , Linfocitos T CD8-positivos/inmunología , Proliferación Celular/fisiología , Células Cultivadas , Humanos , Memoria Inmunológica/inmunología , Células Asesinas Naturales/inmunología , Leucocitos Mononucleares/inmunología , Análisis de Secuencia de ARN/métodos , Transcriptoma/inmunologíaRESUMEN
Cytomegalovirus (CMV) is a major infectious cause of death and disease after transplantation. We have previously demonstrated that the tissue-associated adaptive Vδ2neg γδ T cells are key effectors responding to CMV and associated with recovery, contrasting with their innatelike circulating counterparts, the Vγ9posVδ2pos T cells that respond to phosphoantigens but not to CMV. A third Vγ9negVδ2pos subgroup with adaptive functions has been described in adults. In the current study, we demonstrate that these Vγ9negVδ2pos T cells are also components of the CMV immune response while presenting with distinct characteristics from Vδ2neg γδ T cells. In a cohort of kidney transplant recipients, CMV seropositivity was the unique clinical parameter associated with Vγ9negVδ2pos T-cell expansion and differentiation. Extensive phenotyping demonstrated their substantial cytotoxic potential and activation during acute CMV primary infection or reinfection. In vitro, Vγ9negVδ2pos T cells responded specifically to CMV-infected cells in a T-cell receptor-dependent manner and through strong interferon γ production. Finally, Vγ9negVδ2pos T cells were the only γδ T-cell subset in which expansion was tightly correlated with the severity of CMV disease. To conclude, our results identify a new player in the immune response against CMV and open interesting clinical perspectives for using Vγ9negVδ2pos T cells as an immune marker for CMV disease severity in immunocompromised patients.
Asunto(s)
Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Subgrupos de Linfocitos T/inmunología , Biomarcadores , Línea Celular , Infecciones por Citomegalovirus/fisiopatología , Femenino , Fibroblastos/inmunología , Fibroblastos/virología , Humanos , Huésped Inmunocomprometido , Interferón gamma/biosíntesis , Trasplante de Riñón , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
mTOR inhibitors exert a preventive effect on cytomegalovirus (CMV) disease in CMV seropositive (R+) kidney transplant recipients, but their impact during the curative treatment of CMV disease in high-risk kidney transplant recipients has not been investigated. We aimed to evaluate the efficacy and tolerance of mTOR inhibitors compared with mycophenolic acid in 63 consecutive kidney transplant recipients (80% of D+R-) suffering from CMV disease with a persistent or a recurrent CMV DNAemia. In this monocentric retrospective study, 16 had their treatment converted to mTOR inhibitors and 47 did not. The Kaplan-Meier curves did not show any significant differences in CMV DNAemia eradication (77% vs. 88% respectively; hazard ratio (HR), 1.648 [95% confidence interval (CI), 0.913-2.973]; log-rank test, P = .132), DNAemia recurrence (36% vs. 47%; HR, 1.517 [95% CI, 0.574-4.007]; log-rank test, P = .448) and CMV clinical recurrence (17% vs. 27%; HR, 1.375 [95% CI, 0.340-5.552]; log-rank test, P = .677) between patients who received mTOR inhibitors and those who did not. These results were confirmed in uni- and multivariate time-dependent Cox regressions. In summary, conversion from mycophenolic acid to mTOR inhibitors seems inadequate for improving CMV clearance or in better preventing CMV recurrences during severe or persistent CMV disease.
Asunto(s)
Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , Ácido Micofenólico/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Antivirales/uso terapéutico , Citomegalovirus , Femenino , Humanos , Inmunofenotipificación , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Human γδ T cells comprise a first line of defense through T-cell receptor (TCR) recognition of stressed cells. However, the molecular determinants and stress pathways involved in this recognition are largely unknown. Here we show that exposure of tumor cells to various stress situations led to tumor cell recognition by a Vγ8Vδ3 TCR. Using a strategy that we previously developed to identify antigenic ligands of γδ TCRs, annexin A2 was identified as the direct ligand of Vγ8Vδ3 TCR, and was found to be expressed on tumor cells upon the stress situations tested in a reactive oxygen species-dependent manner. Moreover, purified annexin A2 was able to stimulate the proliferation of a Vδ2neg γδ T-cell subset within peripheral blood mononuclear cells and other annexin A2-specific Vδ2neg γδ T-cell clones could be derived from peripheral blood mononuclear cells. We thus propose membrane exposure of annexin A2 as an oxidative stress signal for some Vδ2neg γδ T cells that could be involved in an adaptive stress surveillance.
Asunto(s)
Anexina A2/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Transducción de Señal , Estrés Fisiológico , Subgrupos de Linfocitos T/metabolismo , Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/farmacología , Línea Celular Tumoral , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/metabolismo , Humanos , Inmunidad Innata , Ligandos , Activación de Linfocitos , Neoplasias/inmunología , Neoplasias/metabolismo , Estrés Oxidativo , Unión Proteica , Receptores de Antígenos de Linfocitos T gamma-delta/antagonistas & inhibidoresRESUMEN
BACKGROUND: Rabbit antithymocyte globulin (rATG) induction is associated with profound immunosuppression, leading to a higher risk of cytomegalovirus (CMV) infection compared with anti-interleukin 2 receptor antibody (anti-IL-2RA). However, this risk, depending on the baseline CMV serological recipient/donor status, is still controversial. METHODS: The CMV DNAemia-free survival between rATG- and anti-IL-2RA-treated patients was analyzed in donor-positive/recipient-negative (D+R-) and recipient-positive (R+) patients in 1 discovery cohort of 559 kidney transplant recipients (KTRs) and 2 independent cohorts (351 and 135 kidney KTRs). The CMV-specific cell-mediated immunity (CMI) at baseline and at different time points after transplantation was assessed using an interferon γ enzyme-linked immunosorbent spot assay. RESULTS: rATG increased the risk of CMV DNAemia in R+ but not in D+R- KTRs. In R+ CMI-positive (CMI+) patients, the CMV DNAemia rate was higher in rATG-treated than in anti-IL-2RA-treated patients; no difference was observed among R+ CMI-negative (CMI-) patients. Longitudinal follow-up demonstrated a deeper depletion of preformed CMV CMI in R+ rATG-treated patients. CONCLUSIONS: D+R- KTRs have the highest risk of CMV DNAemia, but rATG adds no further risk. Among R+ KTRs, we described 3 groups, the least prone being R+CMI+ KTRs without rATG, then R+CMI+ KTRs with rATG, and finally R+CMI- KTRs. CMV serostatus, baseline CMV-specific CMI, and induction therapy may lead to personalized preventive therapy in further studies.
Asunto(s)
Suero Antilinfocítico/inmunología , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Trasplante de Riñón/efectos adversos , Receptores de Trasplantes , Antivirales/uso terapéutico , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Inmunidad Celular , Terapia de Inmunosupresión , Inmunosupresores/administración & dosificación , Interferón gamma , Subunidad alfa del Receptor de Interleucina-2/inmunología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Donantes de TejidosRESUMEN
OBJECTIVES: Adult immunoglobulin A vasculitis (IgAV) is an immune complex small vessel vasculitis. So far, the involvement of T cells in this pathology has been poorly studied. The aim of this study was to analyze T-cell homeostasis as well as cytokine and chemokine concentrations in the blood and tissues of IgAV patients. METHODS: T cells, cytokine and chemokine concentrations were analyzed in peripheral blood using flow cytometry and multiplex assays. T-cell infiltrates in the kidney and the skin were characterized by immunohistochemistry. This study prospectively included 44 adult patients with biopsy-proven IgAV and 24 age- and sex-matched healthy controls. RESULTS: We observed reduced proportions of circulating CXCR5-and CXCR3-expressing memory CD4 T cells at diagnosis but normal values at remission. The plasma levels of Th1-related cytokines (IL-12, IL-27 and IFNγ) and of the TFH-related cytokine, IL-21, were paradoxically not reduced in patients. We observed increased plasma concentrations of the CXCR5 ligand, CXCL13, and of the CXCR3 ligands, CXCL10/11, suggesting a potential relocation of the corresponding T cells into inflamed tissues. We then confirmed the recruitment of CXCR3-expressing T cells into the skin and kidneys. In the skin, T-cell infiltrates mainly co-localized with damaged dermal small vessels. Finally, patients with the largest kidney T-cell infiltrates were also those with the highest proteinuria. CONCLUSION: Altogether, our results strongly suggest that, in IgAV patients, CXCL10/11 orchestrate the recruitment of CXCR3-expressing T cells in injured tissues, contributing to tissue damage and disease activity.
Asunto(s)
Inmunoglobulina A/inmunología , Receptores CXCR3/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Vasculitis/etiología , Vasculitis/metabolismo , Adulto , Complejo Antígeno-Anticuerpo/inmunología , Complejo Antígeno-Anticuerpo/metabolismo , Biomarcadores , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Memoria Inmunológica , Ligandos , Masculino , Unión Proteica , Receptores CXCR3/genética , Receptores CXCR5/metabolismo , Índice de Severidad de la Enfermedad , Vasculitis/diagnósticoRESUMEN
During Plasmodium falciparum infections, erythrocyte-stage parasites inhibit dendritic cell maturation and function, compromising effective antimalarial adaptive immunity. Human Vγ9Vδ2 T cells can act in vitro as antigen-presenting cells (APCs) and induce αß T-cell activation. However, the relevance of this activity in vivo has remained elusive. Because Vγ9Vδ2 T cells are activated during the early immune response against P. falciparum infection, we investigated whether they could contribute to the instruction of adaptive immune responses toward malaria parasites. In P. falciparum-infected patients, Vγ9Vδ2 T cells presented increased surface expression of APC-associated markers HLA-DR and CD86. In response to infected red blood cells in vitro, Vγ9Vδ2 T cells upregulated surface expression of HLA-DR, HLA-ABC, CD40, CD80, CD83, and CD86, induced naive αß T-cell responses, and cross- presented soluble prototypical protein to antigen-specific CD8+ T cells. Our findings qualify Vγ9Vδ2 T cells as alternative APCs, which could be harnessed for therapeutic interventions and vaccine design.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Activación de Linfocitos/inmunología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Linfocitos T/inmunología , Presentación de Antígeno/inmunología , Células Presentadoras de Antígenos/química , Humanos , Fenotipo , Linfocitos T/químicaRESUMEN
Cytomegalovirus (CMV) is a leading infectious cause of morbidity in immune-compromised patients. γδ T cells have been involved in the response to CMV but their role in protection has not been firmly established and their dependency on other lymphocytes has not been addressed. Using C57BL/6 αß and/or γδ T cell-deficient mice, we here show that γδ T cells are as competent as αß T cells to protect mice from CMV-induced death. γδ T cell-mediated protection involved control of viral load and prevented organ damage. γδ T cell recovery by bone marrow transplant or adoptive transfer experiments rescued CD3ε-/- mice from CMV-induced death confirming the protective antiviral role of γδ T cells. As observed in humans, different γδ T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells. This response was observed in the liver and lungs and implicated both CD27+ and CD27- γδ T cells. NK cells were the largely preponderant producers of IFNγ and cytotoxic granules throughout the infection, suggesting that the protective role of γδ T cells did not principally rely on either of these two functions. Finally, γδ T cells were strikingly sufficient to fully protect Rag-/-γc-/- mice from death, demonstrating that they can act in the absence of B and NK cells. Altogether our results uncover an autonomous protective antiviral function of γδ T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new γδ T cell based therapies, especially useful in αß T cell compromised patients.
Asunto(s)
Infecciones por Herpesviridae/inmunología , Inmunidad Celular , Muromegalovirus/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Animales , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/patología , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Linfocitos T/patologíaRESUMEN
Cytomegalovirus (CMV) infection in solid-organ transplantation is associated with increased morbidity and mortality, particularly if a CMV mutant strain with antiviral resistance emerges. Monitoring CMV-specific T cell response could provide relevant information for patient care. We and others have shown the involvement of Vδ2(neg) γδ T cells in controlling CMV infection. Here, we assessed if Vδ2(neg) γδ T cell kinetics in peripheral blood predict CMV infection resolution and emergence of a mutant strain in high-risk recipients of kidney transplants, including 168 seronegative recipients receiving organs from seropositive donors (D+R-) and 104 seropositive recipients receiving antithymocyte globulins (R+/ATG). Vδ2(neg) γδ T cell percentages were serially determined in patients grafted between 2003 and 2011. The growing phase of Vδ2(neg) γδ T cells was monitored in each infected patient, and the expansion rate during this phase was estimated individually by a linear mixed model. A Vδ2(neg) γδ T cell expansion rate of Ë0.06% per day predicted the growing phase. The time after infection at which an expansion rate of 0.06% per day occurred was correlated with the resolution of CMV DNAemia (r=0.91; P<0.001). At 49 days of antiviral treatment, Vδ2(neg) γδ T cell expansion onset was associated with recovery, whereas absence of expansion was associated with recurrent disease and DNAemia. The appearance of antiviral-resistant mutant CMV strains was associated with delayed Vδ2(neg) γδ T cell expansion (P<0.001). In conclusion, longitudinal surveillance of Vδ2(neg) γδ T cells in recipients of kidney transplants may predict CMV infection resolution and antiviral drug resistance.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/inmunología , Trasplante de Riñón , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/inmunología , Linfocitos T , Infecciones por Citomegalovirus/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/virología , Pronóstico , Inducción de RemisiónRESUMEN
Malaria induces potent activation and expansion of the Vγ9Vδ2 subpopulation of γδT cells, which inhibit the Plasmodium falciparum blood cycle through soluble cytotoxic mediators, abrogating merozoite invasion capacity. Intraerythrocytic stages efficiently trigger Vγ9Vδ2 T-cell activation and degranulation through poorly understood mechanisms. P. falciparum blood-stage extracts are known to contain phosphoantigens able to stimulate Vγ9Vδ2 T cells, but how these are presented by intact infected red blood cells (iRBCs) remains elusive. Here we show that, unlike activation by phosphoantigen-expressing cells, Vγ9Vδ2 T-cell activation by intact iRBCs is independent of butyrophilin expression by the iRBC, and contact with an intact iRBC is not required. Moreover, blood-stage culture supernatants proved to be as potent activators of Vγ9Vδ2 T cells as iRBCs. Bioactivity in the microenvironment is attributable to phosphoantigens, as it is dependent on the parasite DOXP pathway, on Vγ9Vδ2 TCR signaling, and on butyrophilin expression by Vγ9Vδ2 T cells. Kinetic studies showed that the phosphoantigens were released at the end of the intraerythrocytic cycle at the time of parasite egress. We document exquisite sensitivity of Vγ9Vδ2 T cells, which respond to a few thousand parasites. These data unravel a novel framework, whereby release of phosphoantigens into the extracellular milieu by sequestered parasites likely promotes activation of distant Vγ9Vδ2 T cells that in turn exert remote antiparasitic functions.
Asunto(s)
Antígenos de Protozoos/inmunología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunología , Subgrupos de Linfocitos T/inmunología , Antígenos de Protozoos/metabolismo , Eritrocitos/parasitología , Humanos , Activación de Linfocitos , Malaria Falciparum/parasitología , Merozoítos/crecimiento & desarrollo , Merozoítos/inmunología , Merozoítos/fisiología , Fosforilación , Plasmodium falciparum/crecimiento & desarrollo , Plasmodium falciparum/fisiología , Proteínas Protozoarias/metabolismo , Subgrupos de Linfocitos T/parasitologíaRESUMEN
The international γδ T cell conference takes place every 2 years. After being held in Denver (USA) in 2004, La Jolla (USA) in 2006, Marseille (France) in 2008, Kiel (Germany) in 2010 and Freiburg (Germany) in 2012, the γδ T cell community gathered this time in Chicago (USA). This conference was organized by Zheng Chen from 16 to 18 May 2014 at his home institution, the University of Illinois College of Medicine, and boasted 180 attendants from all over the world and almost 100 submitted abstracts.
Asunto(s)
Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Autoinmunidad/inmunología , Humanos , Neoplasias/inmunología , Cicatrización de Heridas/inmunologíaRESUMEN
γδ T lymphocytes are involved in the stress response to injured epithelia and in tissue homeostasis by limiting the dissemination of malignant or infected cells and by regulating the nature of the subsequent adaptive immune response. γδ T cells have potent MHC-unrestricted cytotoxicity, a high potential for cytokine release and broad-spectrum recognition of cancer cells, and as such, are attractive effectors for cancer immunotherapy. Current expectations are going beyond ex vivo manipulation of the Vγ9Vδ2 T subset, and target novel γδ T cell subsets, properties or receptors, to harness these unconventional T lymphocytes against cancer. This Opinion article discusses novel aspects of γδ T cell function during the course of anticancer therapies, as well as new avenues for their clinical implementation.