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1.
Nat Immunol ; 21(6): 684-694, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32231301

RESUMEN

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27-CD28-CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27-CD28-CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27-CD28-CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Senescencia Celular/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Citotoxicidad Inmunológica , Perfilación de la Expresión Génica , Humanos , Proteínas de la Membrana/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Proteínas Nucleares/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Células Asesinas Naturales/metabolismo , Transducción de Señal , Fiebre Amarilla/genética , Fiebre Amarilla/inmunología , Fiebre Amarilla/metabolismo , Fiebre Amarilla/virología , Virus de la Fiebre Amarilla/inmunología
2.
Nat Immunol ; 18(3): 354-363, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28114291

RESUMEN

Mitogen-activated protein kinases (MAPKs) including Erk, Jnk and p38 regulate diverse cellular functions and are thought to be controlled by independent upstream activation cascades. Here we show that the sestrins bind to and coordinate simultaneous Erk, Jnk and p38 MAPK activation in T lymphocytes within a new immune-inhibitory complex (sestrin-MAPK activation complex (sMAC)). Whereas sestrin ablation resulted in broad reconstitution of immune function in stressed T cells, inhibition of individual MAPKs allowed only partial functional recovery. T cells from old humans (>65 years old) or mice (16-20 months old) were more likely to form the sMAC, and disruption of this complex restored antigen-specific functional responses in these cells. Correspondingly, sestrin deficiency or simultaneous inhibition of all three MAPKs enhanced vaccine responsiveness in old mice. Thus, disruption of sMAC provides a foundation for rejuvenating immunity during aging.


Asunto(s)
Envejecimiento/inmunología , Linfocitos T CD4-Positivos/fisiología , Proteínas de Choque Térmico/metabolismo , Inmunidad , Inmunosenescencia , Adulto , Anciano , Anciano de 80 o más Años , Animales , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Proteínas de Choque Térmico/genética , Humanos , Inmunidad/genética , Inmunosenescencia/genética , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/metabolismo , Masculino , Ratones , Persona de Mediana Edad , ARN Interferente Pequeño/genética , Transducción de Señal , Adulto Joven
3.
Nat Immunol ; 15(10): 965-72, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25151490

RESUMEN

In T lymphocytes, the mitogen-activated protein kinase (MAPK) p38 regulates pleiotropic functions and is activated by canonical MAPK signaling or the alternative activation pathway downstream of the T cell antigen receptor (TCR). Here we found that senescent human T cells lacked the canonical and alternative pathways for the activation of p38 but spontaneously engaged the metabolic master regulator AMPK to trigger recruitment of p38 to the scaffold protein TAB1, which caused autophosphorylation of p38. Signaling via this pathway inhibited telomerase activity, T cell proliferation and the expression of key components of the TCR signalosome. Our findings identify a previously unrecognized mode for the activation of p38 in T cells driven by intracellular changes such as low-nutrient and DNA-damage signaling (an 'intrasensory' pathway). The proliferative defect of senescent T cells was reversed by blockade of AMPK-TAB1-dependent activation of p38.


Asunto(s)
Proteínas Quinasas Activadas por AMP/inmunología , Proteínas Adaptadoras Transductoras de Señales/inmunología , Linfocitos T CD4-Positivos/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Células Cultivadas , Senescencia Celular/genética , Senescencia Celular/inmunología , Activación Enzimática/inmunología , Femenino , Expresión Génica/inmunología , Humanos , Immunoblotting , Masculino , Persona de Mediana Edad , Fosforilación/inmunología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Telomerasa/genética , Telomerasa/inmunología , Telomerasa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
4.
Trends Immunol ; 37(12): 866-876, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27720177

RESUMEN

As humans live longer, a central concern is to find ways to maintain their health as they age. Immunity declines during ageing, as shown by the increased susceptibility to infection by both previously encountered and new pathogens and by the decreased efficacy of vaccination. It is therefore crucial to understand the mechanisms responsible for this decrease in immunity and to develop new strategies to enhance immune function in older humans. We discuss here how the induction of senescence alters leukocyte, and specifically T cell, function. An emerging concept is that senescence and nutrient sensing-signalling pathways within T cells converge to regulate functional responses, and the manipulation of these pathways may offer new ways to enhance immunity during ageing.


Asunto(s)
Envejecimiento/inmunología , Senescencia Celular , Inmunidad , Linfocitos T/fisiología , Animales , Humanos , Inmunización , Transducción de Señal
5.
J Immunol ; 197(7): 2891-2899, 2016 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27566818

RESUMEN

NK cells are the first line of defense against infected and transformed cells. Defective NK cell activity was shown to increase susceptibility for viral infections and reduce tumor immune-surveillance. With age, the incidence of infectious diseases and malignancy rises dramatically, suggesting that impaired NK cell function might contribute to disease in these individuals. We found an increased frequency of NK cells with high expression of the inhibitory killer cell lectin-like receptor G1 (KLRG1) in individuals >70 y. The role of KLRG1 in ageing is not known, and the mechanism of KLRG1-induced inhibition of NK cell function is not fully understood. We report that NK cells with high KLRG1 expression spontaneously activate the metabolic sensor AMP-activated protein kinase (AMPK) and that activation of AMPK negatively regulates NK cell function. Pre-existing AMPK activity is further amplified by ligation of KLRG1 in these cells, which leads to internalization of the receptor and allows interaction with AMPK. We show that KLRG1 activates AMPK by preventing its inhibitory dephosphorylation by protein phosphatase-2C rather than inducing de novo kinase activation. Finally, inhibition of KLRG1 or AMPK prevented KLRG1-induced activation of AMPK and reductions in NK cell cytotoxicity, cytokine secretion, proliferation, and telomerase expression. This novel signaling pathway links metabolic sensing, effector function, and cell differentiation with inhibitory receptor signaling that may be exploited to enhance NK cell activity during ageing.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Receptores Similares a Lectina de Células NK/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Femenino , Humanos , Células Asesinas Naturales/enzimología , Masculino , Adulto Joven
6.
J Immunol ; 191(7): 3744-52, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23997212

RESUMEN

The cytokine IFN-α is secreted during viral infections and has been shown to inhibit telomerase activity and accelerate T cell differentiation in vivo. However, the mechanism for this inhibition is not clear. In this study, we show that IFN-α inhibits both the transcription and translation of human telomerase reverse transcriptase (hTERT), the catalytic component of telomerase, in activated CD8(+) T cells. This was associated with increased activity of the repressor of hTERT transcription E2 transcription factor and decreased activation of NF-κB that promotes hTERT transcription. However IFN-α did not affect the translocation of hTERT from the cytoplasm to the nucleus. IFN-α also inhibits AKT kinase activation but increases p38 MAPK activity, and both of these events have been shown previously to inhibit telomerase activity. Addition of BIRB796, an inhibitor of p38 activity, to IFN-α-treated cells reversed, in part, the inhibition of telomerase by this cytokine. Therefore, IFN-α can inhibit the enzyme telomerase in CD8(+) T cells by transcriptional and posttranslational mechanisms. Furthermore, the addition of IFN-α to CD8(+)CD27(+)CD28(+) T cells accelerates the loss of both these costimulatory molecules. This suggests that persistent viral infections may contribute to the accumulation of highly differentiated/senescent CD8(+)CD27(-)CD28(-) T cells during aging by promoting IFN-α secretion during repeated episodes of viral reactivation.


Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Interferón-alfa/farmacología , Transducción de Señal/efectos de los fármacos , Telomerasa/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Antígenos CD28/metabolismo , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Factores de Transcripción E2F/metabolismo , Activación Enzimática/efectos de los fármacos , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Telomerasa/metabolismo , Transcripción Genética/efectos de los fármacos , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo
7.
Methods Mol Biol ; 2654: 251-261, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37106187

RESUMEN

Eukaryotes solve the DNA-end replication problem synthesizing hexameric chromosome ends known as telomeres. Recent studies have uncovered unexpected functions of telomeres in linking synaptic signaling and vesicle transport, with at least one pathway directly involved in transferring telomeres through the immune synapse. These emerging forms of cellular communication may originate a new class of antiaging interventions based on telomere transplants.


Asunto(s)
Sinapsis Inmunológicas , Telomerasa , Sinapsis Inmunológicas/metabolismo , Telómero/genética , Telómero/metabolismo , Replicación del ADN , Proteínas de Unión a Telómeros/metabolismo , Senescencia Celular , Telomerasa/genética
8.
Nat Cell Biol ; 24(10): 1461-1474, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36109671

RESUMEN

The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.


Asunto(s)
Telomerasa , Telomerasa/genética , Telomerasa/metabolismo , Memoria Inmunológica , Linfocitos T/metabolismo , Telómero/genética , Telómero/metabolismo , Senescencia Celular/genética
9.
Methods Mol Biol ; 1514: 119-126, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27787797

RESUMEN

Telomerase, a RNA-dependent DNA polymerase that adds telomeric DNA at the 3' ends of eukaryotic chromosomes, is essential for the lifelong preservation of the proliferative potential of antigen specific T lymphocytes. However, senescent T cells that have low telomerase activity, short telomeres and lack of replicative capacity accumulate in old humans, patients with chronic viral infections and cancer. The mechanisms inhibiting telomerase in these cells are poorly understood. Here I describe a strategy that was successfully applied to identify pathways causing telomerase dysfunction in primary human senescent T lymphocytes. Such strategy couples lentiviral vector-based gene manipulations to functional and signaling readouts directly ex vivo, in humans.


Asunto(s)
Senescencia Celular/genética , Biología Molecular/métodos , Linfocitos T/inmunología , Telomerasa/aislamiento & purificación , Proliferación Celular/genética , Senescencia Celular/inmunología , Humanos , Neoplasias/enzimología , Neoplasias/inmunología , Linfocitos T/enzimología , Telomerasa/genética , Telómero/genética
10.
Cell Res ; 26(9): 969-70, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27514702

RESUMEN

Differences in mitochondrial structures determine the metabolic landscape of effector and memory T cell populations in vivo.


Asunto(s)
Memoria Inmunológica , Dinámicas Mitocondriales , Linfocitos T CD8-positivos , Diferenciación Celular , Mitocondrias
11.
J Clin Invest ; 124(9): 4004-16, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25083993

RESUMEN

T cell senescence is thought to contribute to immune function decline, but the pathways that mediate senescence in these cells are not clear. Here, we evaluated T cell populations from healthy volunteers and determined that human CD8+ effector memory T cells that reexpress the naive T cell marker CD45RA have many characteristics of cellular senescence, including decreased proliferation, defective mitochondrial function, and elevated levels of both ROS and p38 MAPK. Despite their apparent senescent state, we determined that these cells secreted high levels of both TNF-α and IFN-γ and showed potent cytotoxic activity. We found that the senescent CD45RA-expressing population engaged anaerobic glycolysis to generate energy for effector functions. Furthermore, inhibition of p38 MAPK signaling in senescent CD8+ T cells increased their proliferation, telomerase activity, mitochondrial biogenesis, and fitness; however, the extra energy required for these processes did not arise from increased glucose uptake or oxidative phosphorylation. Instead, p38 MAPK blockade in these senescent cells induced an increase in autophagy through enhanced interactions between p38 interacting protein (p38IP) and autophagy protein 9 (ATG9) in an mTOR-independent manner. Together, our findings describe fundamental metabolic requirements of senescent primary human CD8+ T cells and demonstrate that p38 MAPK blockade reverses senescence via an mTOR-independent pathway.


Asunto(s)
Autofagia/fisiología , Linfocitos T CD8-positivos/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Complejos Multiproteicos/fisiología , Serina-Treonina Quinasas TOR/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Adulto , Proteínas Relacionadas con la Autofagia , Senescencia Celular , Daño del ADN , Glucólisis , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Potencial de la Membrana Mitocondrial , Proteínas de la Membrana/fisiología , Mitocondrias/fisiología , Fosforilación Oxidativa , Proteínas de Transporte Vesicular/fisiología
12.
Oncoimmunology ; 3(7): e945378, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25954597

RESUMEN

Efficacious antitumor vaccines strongly stimulate cancer-specific effector T cells and counteract the activity of tumor-infiltrating immunosuppressive cells. We hypothesised that combining cytokine expression with silencing programmed cell death ligand 1 (PD-L1) could potentiate anticancer immune responses of lentivector vaccines. Thus, we engineered a collection of lentivectors that simultaneously co-expressed an antigen, a PD-L1-silencing shRNA, and various T cell-polarising cytokines, including interferon γ (IFNγ), transforming growth factor ß (TGFß) or interleukins (IL12, IL15, IL23, IL17A, IL6, IL10, IL4). In a syngeneic B16F0 melanoma model and using tyrosinase related protein 1 (TRP1) as a vaccine antigen, we found that simultaneous delivery of IL12 and a PD-L1-silencing shRNA was the only combination that exhibited therapeutically relevant anti-melanoma activities. Mechanistically, we found that delivery of the PD-L1 silencing construct boosted T cell numbers, inhibited in vivo tumor growth and strongly cooperated with IL12 cytokine priming and antitumor activities. Finally, we tested the capacities of our vaccines to counteract tumor-infiltrating myeloid-derived suppressor cell (MDSC) activities ex vivo. Interestingly, the lentivector co-expressing IL12 and the PD-L1 silencing shRNA was the only one that counteracted MDSC suppressive activities, potentially underlying the observed anti-melanoma therapeutic benefit. We conclude that (1) evaluation of vaccines in healthy mice has no significant predictive value for the selection of anticancer treatments; (2) B16 cells expressing xenoantigens as a tumor model are of limited value; and (3) vaccines which inhibit the suppressive effect of MDSC on T cells in our ex vivo assay show promising and relevant antitumor activities.

13.
Mol Immunol ; 54(2): 181-92, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23287597

RESUMEN

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by a progressive decline of CD4(+) T cells and by other immune disorders that are similar to those observed during aging and which lead eventually to AIDS. One of the mechanisms involved in HIV-1 induced immunodeficiency may be the lack of telomerase induction and the consequent impairment of the potential required for CD4(+) T cell expansion. Telomerase compensates for the progressive telomere loss during cell division and preserves the replicative potential of T lymphocytes after repeated antigenic stimulation. The enzyme is activated by post-translational modifications, such as phosphorylation and also by the nuclear import of its catalytic subunit hTERT from the cytoplasm. In previous studies we found a reduction of telomerase activity in the nucleus of CD4(+) T cells infected with HIV-1 or non-infected but exposed to Tat protein. However, the mechanism for this loss of activity has not been elucidated yet. In the present study, we found that HIV-1 Tat inhibited telomerase activity in CD4(+) T cells by different mechanisms. First, it reduced nuclear levels of hTERT. Secondly, this protein perturbed the AKT pathway and the molecular interaction with the chaperones required for hTERT phosphorylation, nuclear import and activation. These results suggest that in addition to inducing direct cell death, HIV infection may also reduce the replicative potential of non-infected CD4(+) T cells and this may contribute to the overall immunodeficiency in AIDS patients.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Telomerasa/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Línea Celular , Núcleo Celular/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Activación Enzimática , Regulación de la Expresión Génica , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Telómero/genética , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Transcripción Genética , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/inmunología
14.
Oncoimmunology ; 2(10): e26148, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-24244902

RESUMEN

Since dendritic cells operate as professional antigen-presenting cells (APCs) and hence are capable of jumpstarting the immune system, they have been exploited to develop a variety of immunotherapeutic regimens against cancer. In the few past years, myeloid-derived suppressor cells (MDSCs) have been shown to mediate robust immunosuppressive functions, thereby inhibiting tumor-targeting immune responses. Thus, we propose that the immunomodulatory activity of MDSCs should be carefully considered for the development of efficient anticancer immunotherapies.

15.
Virus Res ; 176(1-2): 1-15, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23726846

RESUMEN

Our work over the past eight years has focused on the use of HIV-1 lentiviral vectors (lentivectors) for the genetic modification of dendritic cells (DCs) to control their functions in immune modulation. DCs are key professional antigen presenting cells which regulate the activity of most effector immune cells, including T, B and NK cells. Their genetic modification provides the means for the development of targeted therapies towards cancer and autoimmune disease. We have been modulating with lentivectors the activity of intracellular signalling pathways and co-stimulation during antigen presentation to T cells, to fine-tune the type and strength of the immune response. In the course of our research, we have found unexpected results such as the surprising immunosuppressive role of anti-viral signalling pathways, and the close link between negative co-stimulation in the immunological synapse and T cell receptor trafficking. Here we review our major findings and put them into context with other published work.


Asunto(s)
Células Dendríticas/inmunología , Vectores Genéticos , VIH-1/genética , Inmunomodulación , Enfermedades Autoinmunes/terapia , Células Dendríticas/virología , Humanos , Inmunoterapia/métodos , Neoplasias/terapia
16.
Immunol Endocr Metab Agents Med Chem ; 12(3): 224-235, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22945252

RESUMEN

One of the key roles of the immune system is the identification of potentially dangerous pathogens or tumour cells, and raising a wide range of mechanisms to eliminate them from the organism. One of these mechanisms is activation and expansion of antigen-specific cytotoxic T cells, after recognition of antigenic peptides on the surface of antigen presenting cells such as dendritic cells (DCs). However, DCs also process and present autoantigens. Therefore, antigen presentation has to occur in the appropriate context to either trigger immune responses or establishing immunological tolerance. This is achieved by co-stimulation of T cells during antigen presentation. Co-stimulation consists on the simultaneous binding of ligand-receptor molecules at the immunological synapse which will determine the type and extent of T cell responses. In addition, the type of cytokines/chemokines present during antigen presentation will influence the polarisation of T cell responses, whether they lead to tolerance, antibody responses or cytotoxicity. In this review, we will focus on approaches manipulating co-stimulation during antigen presentation, and the role of cytokine stimulation on effective T cell responses. More specifically, we will address the experimental strategies to interfere with negative co-stimulation such as that mediated by PD-L1 (Programmed cell death 1 ligand 1)/PD-1 (Programmed death 1) to enhance anti-tumour immunity.

17.
J Clin Cell Immunol ; S122012 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-23525238

RESUMEN

For T cell activation, three signals have to be provided from the antigen presenting cell; Signal 1 (antigen recognition), signal 2 (co-stimulation) and signal 3 (cytokine priming). Blocking negative co-stimulation during antigen presentation to T cells is becoming a promising therapeutic strategy to enhance cancer immunotherapy. Here we will focus on interference with PD-1/PD-L1 negative co-stimulation during antigen presentation to T cells as a therapeutic approach. We will discuss the potential mechanisms and the therapeutic consequences by which interference/inhibition with this interaction results in anti-tumour immunity. Particularly, we will comment on whether blocking negative co-stimulation provides differentiation signals to T cells undergoing antigen presentation. A major dogma in immunology states that T cell differentiation signals are given by cytokines and chemokines (signal 3) rather than co-stimulation (signal 2). We will discuss whether this is the case when blocking PD-L1/PD-1 negative co-stimulation.

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