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T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8 + T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8 + T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A , remain ‘epigenetically scarred.’ T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells. The degree of plasticity in the epigenetic landscape of exhausted T cells has been unclear. Sen and colleagues find that exhausted CD8 + T cells demonstrate a stable core epigenetic exhaustion signature that persists independent of inflammation or viral antigen.

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8 + T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory. Lauer and colleagues examine CD8 + T cells following cure of human hepatitis C virus (HCV) infection. CD8 + T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional exhaustion that is maintained even after antigen stimulus is removed.

Objectives Diffuse large B‐cell lymphoma (DLBCL) constitutes 30–40% of non‐Hodgkin lymphoma cases. Despite therapeutic advances, persistence of relapsed cases has been linked to the complex tumor microenvironment (TME) and its interactions with lymphoma cells. In particular, characterising T‐cell subsets, including rare cell types, and their interplay with the remaining TME is crucial for unravelling DLBCL pathogenesis and refining therapeutic strategies. Methods Using flow and spectral cytometry with unsupervised analysis, we investigated T‐cell subpopulations across DLBCL biopsies and control lymph nodes (LN). We also inferred communication pathways between T cells and other immune cells in the TME based on the correlation of ligand–receptor expression. Results Our analysis revealed a higher frequency of CD8+ follicular regulatory T (Tfr) cells in DLBCL biopsies compared to control LN. These cells exhibited an effector‐memory phenotype (CD45RA− CCR7−), expressed follicular markers (PD‐1+ CXCR5+) and had a regulatory profile (CD127− CD25+) along with an activation/co‐stimulatory signature (HLA‐DR+, ICOS+, CD95+). Correlation analysis highlighted a co‐stimulatory interaction between lymphoma B cells and CD8+ Tfr cells through the ICOS/ICOSL pathway, which may contribute to a protumor effect. Validation in independent scRNAseq and flow cytometry datasets confirmed the notable prevalence of CD8+ Tfr cells in DLBCL biopsies. Conclusions Our study highlights the utility of high‐dimensional computational cytometry in elucidating T‐cell subpopulations, including an increased frequency of CD8+ follicular regulatory T cells and their communication patterns within the DLBCL TME. This unbiased approach sheds light on novel cellular mechanisms in DLBCL, uncovering potential targets and biomarkers for immunotherapy. In this study, we employed high‐dimensional flow and spectral cytometry with unsupervised analysis to characterise T‐cell subsets in diffuse large B‐cell lymphoma (DLBCL) biopsies compared to control lymph nodes. We identified an increased frequency of CD8+ follicular regulatory T cells in DLBCL, a finding validated across independent scRNAseq and flow cytometry datasets, highlighting their consistent presence across cohorts and potential relevance to disease biology.

Although association between CMV infection and allograft rejection is well admitted, the precise mechanisms involved remain uncertain. Here, we report the characterization of an alloreactive HLA-E-restricted CD8 T cell population that was detected in the PBL of a kidney transplant patient after its CMV conversion. This monoclonal CD8 T cell population represents a sizable fraction in the blood (3% of PBL) and is characterized by an effector-memory phenotype and the expression of multiple NK receptors. Interestingly, these unconventional T cells display HLA-E-dependent reactivity against peptides derived from the leader sequences of both various HCMV-UL40 and allogeneic classical HLA-I molecules. Consequently, while HLA-E-restricted CD8 T cells have potential to contribute to the control of CMV infection in vivo, they may also directly mediate graft rejection through recognition of peptides derived from allogeneic HLA-I molecules on graft cells. Therefore, as HLA-E expression in nonlymphoid organs is mainly restricted to endothelial cells, we investigated the reactivity of this HLA-E-restricted T cell population towards allogeneic endothelial cells. We clearly demonstrated that CMV-associated HLA-E-restricted T cells efficiently recognized and killed allogeneic endothelial cells in vitro. Moreover, our data indicate that this alloreactivity is tightly regulated by NK receptors, especially by inhibitory KIR2DL2 that strongly prevents TCR-induced activation through recognition of HLA-C molecules. Hence, a better evaluation of the role of CMV-associated HLA-E-restricted T cells in transplantation and of the impact of HLA-genotype, especially HLA-C, on their alloreactivity may determine whether they indeed represent a risk factor following organ transplantation.

MICA are major histocompatibility complex class I-related molecules, expressed by endothelial cells (ECs), that may be targets for alloantibodies and NKG2D-expressing natural killer (NK) and T effector cells in organ allografts. This study shows that basal levels of MICA expressed on vascular ECs is sufficient to functionally modulate the expression and activity of the immunoreceptor NKG2D in allogeneic NK cells. We found that MICA expression is differentially regulated at the EC surface in response to cytokines. TNFa upregulates MICA while IFNγ significantly decreases MICA at the EC surface. Both cytokines induce the release of soluble MICA by ECs. Modulation of NKG2D correlates with the MICA level on the EC surface. Glycosylation and metalloproteinase activities account for major post-transcriptional mechanisms controlling MICA level and the function in ECs. Our results indicate that, in addition to the NFγB pathway, the mitogen-activated protein kinase pathways JNK, ERK1/2 and p38 are key signaling pathways in the control of MICA by the cytokines. Finally, we show that EC proliferation mediated by FGF-2 or wound healing increases the MICA level. Together, our data suggest that inflammation and proliferation regulate endothelial MICA expression and shedding, enabling ECs to modulate NKG2D activity on effector NK and T cells, and provide further evidence of a role for ECs in immunoregulation.

Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8⁺ T cells and show that it is distinct from functional memory CD8⁺ T cells. Exhausted CD8⁺ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing snows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8⁺ T cells.

ObjectiveChronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible. Developing T cell-based therapies able to achieve functional cure will require identification of the requirements for a successful T cell response against HBV and the relative contribution of individual T cell specificities to HBV control.DesignThe phenotype and function of HBV-specific T cells were studied directly ex vivo using fluorochrome-labelled multimers. We studied multiple HBV-specific T cell specificities targeting different HBV proteins in individuals with either an acute self-limiting or chronic HBV infection.ResultsWe detected strong T cell responses targeting multiple HBV viral proteins in acute self-limiting and low-frequency core and polymerase-specific T cells in chronic infection. Expression of the T cell inhibitory receptor PD-1, as well as T cell differentiation, T cell function and T cell regulation differed by stages and outcomes of infection. In addition, these features differed significantly between T cells targeting different HBV specificities.ConclusionHBV-specific T cells with different target specificities are characterised by distinct phenotypical and functional profiles. These results have direct implications for the design of immunological studies in HBV infection, and are potentially relevant for informing immunotherapeutic approaches to induce functional cure.

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8.sup.+ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory.

Background. BK polyomavirus (BKPyV) frequently reactivates in kidney transplant recipients during immunosuppressive therapy and triggers BKPyV-associated nephropathy and graft rejection. Determining effective risk factors for BKPyV reactivation is required to achieve efficient prevention. Methods. This study investigated the role of major histocompatibility complex (MHC) class I—related chain A (MICA) in BKPyV reactivation in a cohort of 144 transplant donor/recipient pairs, including recipients with no reactivation (controllers) and those with mild (virurics) or severe (viremics) BKPyV reactivation after graft receipt. Results. We show that, in the kidney, MICA is predominantly expressed in tubule epithelial cells, the natural targets of BKPyV, questioning a role for MICA in the immune control of BKPyV infection. Focusing on MICA genotype, we found a lower incidence of BKPyV reactivation in recipients of a renal graft from a donor carrying the MICA A5.1 mutant, which encodes a truncated nonconventional MICA. We established that a mismatch for MICA A5.1 between transplant donor and recipient is critical for BKPyV reactivation and BKPyV-associated nephropathy. Functionally, we found that a low prevalence of BKPyV reactivation was associated with elevated an ti-MICA sensitization and reduced plasma level of soluble MICA in recipients, 2 potential effector mechanisms. Discussions.These findings identify the MHC-related MICA as an immunogenetic factor that may functionally influence anti-BKPyV immune responses and infection outcomes.

Zika virus (ZIKV) is a flavivirus that is closely related to other human pathogens, such as dengue virus (DENV) 1 . Primary transmission usually involves Aedes aegypti , which has expanded its distribution range considerably 2 , although rarer infection routes, including mother-to-fetus transmission, sexual contact and blood transfusion, have also been observed 3 – 7 . Primary ZIKV infection is usually asymptomatic or mild in adults, with quickly resolved blood viraemia, but ZIKV might persist for months in saliva, urine, semen, breast milk and the central nervous system 8 – 12 . During a recent ZIKV outbreak in South America, substantial numbers of neurological complications, such as Guillain–Barré syndrome, were reported 13 , 14 together with cases of microcephaly and associated developmental problems in infants born to women infected with ZIKV during pregnancy 15 – 20 , highlighting the clinical importance of this infection. Analyses of the human immune response to ZIKV are lacking 21 – 28 , but the recent outbreak has provided an opportunity to assess ZIKV immunity using current immunological methods. Here, we comprehensively assess the acute innate and adaptive immune response to ZIKV infection in ten women who were recruited during early infection and followed through reconvalescence. We define a cascade of events that lead to immunological control of ZIKV, with previous exposure to DENV impacting some, but not all, mediators of antiviral immunity. This work reports an analysis of primary and secondary immune responses in ten women infected with ZIKV for 224 days following an acute symptomatic Zika virus infection. CD4 + T-cell responses broadly targeted the whole Zika genome, whereas CD8 + T cells were strongly biased towards non-structural proteins.