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1.
Nat Immunol ; 21(9): 1070-1081, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32661361

RESUMEN

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


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Traslado Adoptivo , Animales , Diferenciación Celular , Linaje de la Célula , Plasticidad de la Célula , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética
2.
Nat Immunol ; 19(6): 538-546, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29777219

RESUMEN

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


Asunto(s)
Memoria Inmunológica/inmunología , Neoplasias/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Humanos , Ratones
3.
Nat Immunol ; 17(12): 1467-1478, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27776108

RESUMEN

Tissue-resident memory T cells (TRM cells) in the airways mediate protection against respiratory infection. We characterized TRM cells expressing integrin αE (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung TRM cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint. A distinct set of transcription factors was active in CD103+ TRM cells, including Notch. Genetic and pharmacological experiments with mice revealed that Notch activity was required for the maintenance of CD103+ TRM cells. We have thus identified specialized programs underlying the residence, persistence, vigilance and tight control of human lung TRM cells.


Asunto(s)
Linfocitos T CD8-positivos/fisiología , Memoria Inmunológica , Subtipo H3N2 del Virus de la Influenza A/inmunología , Pulmón/inmunología , Infecciones por Orthomyxoviridae/inmunología , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Infecciones del Sistema Respiratorio/inmunología , Animales , Antígenos CD/metabolismo , Células Cultivadas , Femenino , Humanos , Cadenas alfa de Integrinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Receptor Notch1/genética , Receptor Notch2/genética
4.
Immunity ; 48(5): 1046-1059.e6, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29752063

RESUMEN

To obtain a molecular definition of regulatory T (Treg) cell identity, we performed proteomics and transcriptomics on various populations of human regulatory and conventional CD4+ T (Tconv) cells. A protein expression signature was identified that defines all Treg cells, and another signature that defines effector Treg cells. These signatures could not be extrapolated from transcriptome data. Unique cell-biological and metabolic features in Treg cells were defined, as well as specific adaptations in cytokine, TCR, and costimulatory receptor signaling pathways. One such adaptation-selective STAT4 deficiency-prevented destabilization of Treg cell identity and function by inflammatory cytokines, while these signals could still induce critical transcription factors and homing receptors via other pathways. Furthermore, our study revealed surface markers that identify FOXP3+CD4+ T cells with distinct functional properties. Our findings suggest that adaptation in signaling pathways protect Treg cell identity and present a resource for further research into Treg cell biology.


Asunto(s)
Adaptación Fisiológica , Proteómica/métodos , Transducción de Señal , Linfocitos T Reguladores/metabolismo , Western Blotting , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Células HEK293 , Humanos , Espectrometría de Masas , Receptores de Antígenos de Linfocitos T/metabolismo
5.
Nat Immunol ; 18(8): 870-872, 2017 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-28722713
6.
Nat Immunol ; 13(9): 864-71, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22885984

RESUMEN

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


Asunto(s)
Diferenciación Celular/genética , Células T Asesinas Naturales/citología , Células T Asesinas Naturales/inmunología , Secuencia de Aminoácidos , Animales , Diferenciación Celular/inmunología , Citometría de Flujo , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Filogenia , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genética
8.
J Immunol ; 208(2): 384-395, 2022 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-34937744

RESUMEN

CD4+CD25+FOXP3+ regulatory T (Treg) cells control immunological tolerance. Treg cells are generated in the thymus (tTreg) or in the periphery. Their superior lineage fidelity makes tTregs the preferred cell type for adoptive cell therapy (ACT). How human tTreg cells develop is incompletely understood. By combining single-cell transcriptomics and flow cytometry, we in this study delineated three major Treg developmental stages in the human thymus. At the first stage, which we propose to name pre-Treg I, cells still express lineage-inappropriate genes and exhibit signs of TCR signaling, presumably reflecting recognition of self-antigen. The subsequent pre-Treg II stage is marked by the sharp appearance of transcription factor FOXO1 and features induction of KLF2 and CCR7, in apparent preparation for thymic exit. The pre-Treg II stage can further be refined based on the sequential acquisition of surface markers CD31 and GPA33. The expression of CD45RA, finally, completes the phenotype also found on mature recent thymic emigrant Treg cells. Remarkably, the thymus contains a substantial fraction of recirculating mature effector Treg cells, distinguishable by expression of inflammatory chemokine receptors and absence of CCR7. The developmental origin of these cells is unclear and warrants caution when using thymic tissue as a source of stable cells for ACT. We show that cells in the major developmental stages can be distinguished using the surface markers CD1a, CD27, CCR7, and CD39, allowing for their viable isolation. These insights help identify fully mature tTreg cells for ACT and can serve as a basis for further mechanistic studies into tTreg development.


Asunto(s)
Diferenciación Celular/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Timocitos/citología , Timo/citología , Células Cultivadas , Preescolar , Proteína Forkhead Box O1/metabolismo , Humanos , Tolerancia Inmunológica/inmunología , Factores de Transcripción de Tipo Kruppel/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Glicoproteínas de Membrana/metabolismo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , RNA-Seq/métodos , Receptores CCR7/metabolismo , Análisis de la Célula Individual , Timo/inmunología , Transcriptoma/genética , Secuenciación del Exoma
9.
Eur J Immunol ; 52(3): 389-403, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34897659

RESUMEN

iNKT cells are CD1d-restricted T cells that play a pro-inflammatory or regulatory role in infectious and autoimmune diseases. Thymic precursors of iNKT cells eventually develop into distinct iNKT1, iNKT2, and iNKT17 lineages in the periphery. It remains unclear whether iNKT cells retain developmental potential after lineage commitment. iNKT cells acquire a similar phenotype as tissue-resident memory T cells, suggesting that they also differentiate along a trajectory that enables them to persist in peripheral tissues. Here, we addressed whether lineage commitment and memory differentiation are parallel or sequential developmental programs of iNKT cells. We defined three subsets of peripheral iNKT cells using CD62L and CD69 expression that separate central, effector, and resident memory phenotype cells. The majority of iNKT1 cells displayed a resident phenotype in contrast to iNKT2 and iNKT17 cells. The transcription factor Hobit, which is upregulated in iNKT cells, plays an essential role in their development together with its homolog Blimp-1. Hobit and Blimp-1 instructed the differentiation of central memory iNKT cells into resident memory iNKT cells, but did not impact commitment into iNKT1, iNKT2, or iNKT17 lineages. Thus, we conclude that memory differentiation and the establishment of residency occur after lineage commitment through a Hobit and Blimp-1-driven transcriptional program.


Asunto(s)
Células T Asesinas Naturales , Animales , Diferenciación Celular , Regulación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Fenotipo , Factores de Transcripción/metabolismo
10.
Eur J Immunol ; 52(7): 1095-1111, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35389518

RESUMEN

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


Asunto(s)
Linfocitos T CD8-positivos , Memoria Inmunológica , Coriomeningitis Linfocítica , Virus de la Coriomeningitis Linfocítica , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de Transcripción , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/patología , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Factor 1 de Unión al Dominio 1 de Regulación Positiva/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo
11.
Eur J Immunol ; 50(10): 1515-1524, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32390174

RESUMEN

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


Asunto(s)
Acetaminofén/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Hígado/patología , Células T Asesinas Naturales/fisiología , Receptores Purinérgicos P2X7/metabolismo , Acetaminofén/administración & dosificación , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Tolerancia Inmunológica , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Purinérgicos P2X7/genética
12.
Eur J Immunol ; 50(12): 1998-2012, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33073359

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. Understanding the immune response that provides specific immunity but may also lead to immunopathology is crucial for the design of potential preventive and therapeutic strategies. Here, we characterized and quantified SARS-CoV-2-specific immune responses in patients with different clinical courses. Compared to individuals with a mild clinical presentation, CD4+ T-cell responses were qualitatively impaired in critically ill patients. Strikingly, however, in these patients the specific IgG antibody response was remarkably strong. Furthermore, in these critically ill patients, a massive influx of circulating T cells into the lungs was observed, overwhelming the local T-cell compartment, and indicative of vascular leakage. The observed disparate T- and B-cell responses could be indicative of a deregulated immune response in critically ill COVID-19 patients.


Asunto(s)
Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , COVID-19/inmunología , Inmunoglobulina G/inmunología , SARS-CoV-2/inmunología , Adulto , Anciano , Linfocitos B/patología , Linfocitos T CD4-Positivos/patología , COVID-19/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
13.
Eur J Immunol ; 49(5): 694-708, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30883723

RESUMEN

During acute viral infections in mice, IL-7Rα and KLRG1 together are used to distinguish the short-lived effector cells (SLEC; IL-7Rαlo KLRGhi ) from the precursors of persisting memory cells (MPEC; IL-7Rαhi KLRG1lo ). We here show that these markers can be used to define distinct subsets in the circulation and lymph nodes during the acute phase and in "steady state" in humans. In contrast to the T cells in the circulation, T cells derived from lymph nodes hardly contain any KLRG1-expressing cells. The four populations defined by IL-7Rα and KLRG1 differ markedly in transcription factor, granzyme and chemokine receptor expression. When studying renal transplant recipients experiencing a primary hCMV and EBV infection, we also found that after viral control, during latency, Ki-67-negative SLEC can be found in the peripheral blood in considerable numbers. Thus, combined analyses of IL-7Rα and KLRG1 expression on human herpes virus-specific CD8+ T cells can be used to separate functionally distinct subsets in humans. As a noncycling IL-7Rαlo KLRG1hi population is abundant in healthy humans, we conclude that this combination of markers not only defines short-lived effector cells during the acute response but also stable effector cells that are formed and remain present during latent herpes infections.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Expresión Génica , Lectinas Tipo C/genética , Receptores Inmunológicos/genética , Receptores de Interleucina-7/genética , Adulto , Citomegalovirus/inmunología , Perfilación de la Expresión Génica , Antígenos HLA/genética , Antígenos HLA/inmunología , Herpes Simple/inmunología , Herpes Simple/virología , Humanos , Huésped Inmunocomprometido , Memoria Inmunológica , Inmunofenotipificación , Lectinas Tipo C/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Activación de Linfocitos , Persona de Mediana Edad , Receptores Inmunológicos/metabolismo , Receptores de Interleucina-7/metabolismo , Simplexvirus/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Adulto Joven
14.
Immunity ; 35(1): 97-108, 2011 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-21763160

RESUMEN

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


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/inmunología , Especificidad del Receptor de Antígeno de Linfocitos T , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Animales , Variación Antigénica , Antígenos Virales/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/virología , Células Clonales , Humanos , Memoria Inmunológica , Virus de la Influenza A/patogenicidad , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad del Receptor de Antígeno de Linfocitos T/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
15.
Transpl Int ; 33(9): 1116-1127, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32480425

RESUMEN

The impact of primary cytomegalovirus infection (pCMV) on renal allograft function and histology is controversial. We evaluated the influence on incidence of acute rejection, allograft loss, allograft function and interstitial fibrosis/tubular atrophy (IF/TA). Retrospective case-control study, recipients transplanted between 2000 and 2014. Risk of acute rejection and allograft loss for those who experienced pCMV infection compared with those who did not, within an exposure period of two months after transplantation. Besides, its influence on allograft function and histology at one to three years after transplantation. Of 113 recipients experienced pCMV infection, 306 remained CMV seronegative. pCMV infection in the exposure period could not be proven as increasing the risk for acute rejection [HR = 2.18 (95% CI 0.80-5.97) P = 0.13] or allograft loss [HR = 1.11 (95%CI 0.33-3.72) P = 0.87]. Combination of pCMV infection and acute rejection posed higher hazard for allograft loss than acute rejection alone [HR = 3.69 (95% CI 1.21-11.29) P = 0.02]. eGFR(MDRD) values did not significantly differ at years one [46 vs. 50], two [46 vs. 51] and three [46 vs. 52]. No association between pCMV infection and IF/TA could be demonstrated [OR = 2.15 (95%CI 0.73-6.29) P = 0.16]. pCMV infection was not proven to increase the risk for acute rejection or allograft loss. However, it increased the risk for rejection-associated allograft loss. In remaining functioning allografts, it was not significantly associated with decline in function nor with presence of IF/TA.


Asunto(s)
Infecciones por Citomegalovirus , Trasplante de Riñón , Estudios de Casos y Controles , Infecciones por Citomegalovirus/epidemiología , Rechazo de Injerto/etiología , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Factores de Riesgo
16.
Eur J Immunol ; 48(10): 1644-1662, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30051906

RESUMEN

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


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factores de Transcripción/genética , Animales , Células Cultivadas , Regulación de la Expresión Génica/inmunología , Granzimas/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células T Asesinas Naturales/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/inmunología , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo
17.
Immunity ; 32(6): 754-65, 2010 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-20620942

RESUMEN

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


Asunto(s)
Apoptosis/inmunología , Activación de Linfocitos/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Separación Celular , Células Clonales , Citometría de Flujo , Expresión Génica , Perfilación de la Expresión Génica , Immunoblotting , Inmunohistoquímica , Inmunoprecipitación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Receptores de Antígenos de Linfocitos T/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/inmunología
18.
PLoS Pathog ; 12(10): e1005903, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27723787

RESUMEN

Polyomavirus BK (BKPyV) frequently reactivates in immunosuppressed renal transplant recipients (RTRs) and may lead to graft loss due to BKPyV-induced interstitial nephritis (BKVN). Little is known on the differentiation of CD8+ T cells targeting BKPyV in RTRs. Here we investigated whether BKPyV-specific CD8+ T cell differentiation differs in RTRs with varying degrees of BKPyV reactivation and/or BKVN. Using combinatorial encoding with tetramers carrying BKPyV major capsid protein (VP1) and large T antigen protein (LTAG) epitopes, we investigated CD8+ T cell responses to BKPyV in longitudinally obtained PBMC samples from 46 HLA-A02-positive RTRs and 20 healthy adults. We were also able to isolate BKPyV-specific CD8+ T cells from five renal allografts, two of which were affected by BKVN. Before transplantation, BKPyV-specific CD8+ T cells targeting VP1 and LTAG epitopes appeared predominantly as central-memory and CD27+/CD28+ effector-memory (TEM), and naïve-like PD-1-expressing cells, respectively. After viral reactivation, BKPyV-specific CD8+ T cells assumed CD28- TEM and TEMRA states in patients who were able to control BKPyV, whereas differentiation lagged behind in patients with severe viral reactivation or BKVN. Furthermore, VP1-specific CD69+/CD103+ tissue-resident memory (TRM) cells accumulated in BKVN-affected allografts but lacked signs of effector differentiation. In contrast, granzyme B-expressing effector cells were detected in allografts not affected by BKVN. In conclusion, effector-memory differentiation of BKPyV-specific CD8+ T cells in patients with high viral load or BKVN is impaired. Further characterization of the specific mechanisms behind this altered cellular differentiation is necessary to develop therapies that can prevent the emergence of BKVN.


Asunto(s)
Virus BK , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Trasplante de Riñón , Infecciones por Polyomavirus/inmunología , Infecciones Tumorales por Virus/inmunología , Activación Viral/inmunología , Adulto , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Antígeno HLA-A2 , Humanos , Huésped Inmunocomprometido/inmunología , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Receptores de Trasplantes
19.
PLoS Pathog ; 11(3): e1004675, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25738498

RESUMEN

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


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Inmunidad Celular , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Ligando de CD40/genética , Ligando de CD40/inmunología , Linfocitos T CD8-positivos/patología , Enfermedad Crónica , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/patología , Ratones , Ratones Transgénicos , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Linfocitos T Colaboradores-Inductores/patología
20.
J Hepatol ; 64(3): 539-46, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26505119

RESUMEN

BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is characterized by functional impairment of HBV-specific T cells. Understanding the mechanisms behind T cell dysfunction and restoration is important for the development of optimal treatment strategies. METHODS: In this study we have first analysed the phenotype and function of HBV-specific T cells in patients with low viral load (HBV DNA <20,000IU/ml) and spontaneous control over the virus. Subsequently, we assessed HBV-specific T cells in patients with high viral load (HBV DNA >17,182IU/ml) treated with peginterferon/adefovir combination therapy who had various treatment outcomes. RESULTS: HBV-specific T cells could be detected directly ex vivo in 7/22 patients with low viral load. These showed an early differentiated memory phenotype with reduced ability to produce IL-2 and cytotoxic molecules such as granzyme B and perforin, but with strong proliferative potential. In a cohort of 28 chronic hepatitis B patients with high viral load treated with peginterferon and adefovir, HBV-specific T cells could not be detected directly ex vivo. However, HBV-specific T cells could be selectively expanded in vitro in patients with therapy-induced HBsAg clearance (HBsAg loss n=7), but not in patients without HBsAg clearance (n=21). Further analysis of HBV-specific T cell function with peptide pools showed broad and efficient antiviral responses after therapy. CONCLUSIONS: Our results show that peginterferon based combination therapy can induce HBV-specific T cell restoration. These findings may help to develop novel therapeutic strategies to reconstitute antiviral functions and enhance viral clearance.


Asunto(s)
Antivirales/administración & dosificación , Hepatitis B Crónica/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Citocinas/biosíntesis , Citotoxicidad Inmunológica , Quimioterapia Combinada , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Humanos , Interferones/administración & dosificación , Masculino , Persona de Mediana Edad , Carga Viral
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