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Exhausted CD8+ T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection.

ABSTRACT: Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+ T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8+ T cell signaling and function in vivo.

SUBMITTER: Sandu I

PROVIDER: S-EPMC7479152 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Exhausted CD8+ T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection.

Sandu Ioana I Cerletti Dario D Claassen Manfred M Oxenius Annette A

Nature communications 20200908 1

Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+</ ...[more]

PMID: 32901001

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Project description:CD8+ cytotoxic T lymphocytes (CTLs) exert potent antiviral activity after HIV/SIV infection. However, efforts to harness the antiviral efficacy of CTLs for HIV/SIV prophylaxis and therapy have been severely hindered by two major problems: viral escape and exhaustion. By contrast, CTLs directed against human cytomegalovirus (HCMV), a ubiquitous chronic herpesvirus, seldom select for escape mutations and remain functional and refractory to exhaustion during chronic HCMV and HIV infection. Recently, attempts have been made to retarget HCMV-specific CTLs for cancer immunotherapy. We speculate that such a strategy may also be beneficial in the context of HIV/SIV infection, facilitating CTL-mediated control of HIV/SIV replication. As a preliminary assessment of the validity of this approach, we investigated the phenotypes and functionality of rhesus CMV (RhCMV)-specific CTLs in SIVmac239-infected Indian rhesus macaques (RMs), a crucial HIV animal model system. We recently identified two immunodominant, Mamu-A∗02-restricted CTL epitopes derived from RhCMV proteins and sought to evaluate the phenotypic and functional characteristics of these CTL populations in chronic SIVmac239 infection. We analyzed and directly compared RhCMV- and SIVmac239-specific CTLs during SIVmac239 infection in a cohort of Mamu-A∗01 + and Mamu-A∗02 + RMs. CTL populations specific for at least one of the RhCMV-derived CTL epitopes were detected in ten of eleven Mamu-A∗02 + animals tested, and both populations were detected in five of these animals. Neither RhCMV-specific CTL population exhibited significant changes in frequency, memory phenotype, granzyme B expression, exhaustion marker (PD-1 and CTLA-4) expression, or polyfunctionality between pre- and chronic SIVmac239 infection timepoints. In chronic SIVmac239 infection, RhCMV-specific CTLs exhibited higher levels of granzyme B expression and polyfunctionality, and lower levels of exhaustion marker expression, than SIVmac239-specific CTLs. Additionally, compared to SIVmac239-specific CTLs, greater proportions of RhCMV-specific CTLs were of the terminally differentiated effector memory phenotype (CD28- CCR7-) during chronic SIVmac239 infection. These results suggest that, in contrast to SIVmac239-specific CTLs, RhCMV-specific CTLs maintain their phenotypes and cytolytic effector functions during chronic SIVmac239 infection, and that retargeting RhCMV-specific CTLs might be a promising SIV immunotherapeutic strategy.

Project description:Acute and chronic viral infections result in the differentiation of effector and exhausted T cells with functional and phenotypic differences that dictate whether the infection is cleared or progresses to chronicity. High CD38 expression has been observed on CD8+ T cells across various viral infections and tumors in patients, suggesting an important regulatory function for CD38 on responding T cells. Here, we show that CD38 expression was increased and sustained on exhausted CD8+ T cells following chronic lymphocytic choriomeningitis virus (LCMV) infection, with lower levels observed on T cells from acute LCMV infection. We uncovered a cell-intrinsic role for CD38 expression in regulating the survival of effector and exhausted CD8+ T cells. We observed increased proliferation and function of Cd38-/- CD8+ progenitor exhausted T cells compared to those of wild-type (WT) cells. Furthermore, decreased oxidative phosphorylation and glycolytic potential were observed in Cd38-/- CD8+ T cells during chronic but not acute LCMV infection. Our studies reveal that CD38 has a dual cell-intrinsic function in CD8+ T cells, where it decreases proliferation and function yet supports their survival and metabolism. These findings show that CD38 is not only a marker of T cell activation but also has regulatory functions on effector and exhausted CD8+ T cells. IMPORTANCE Our study shows how CD38 expression is regulated on CD8+ T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8+ T cells during chronic viral infection compared to levels during acute viral infection. Deleting CD38 had an important cell-intrinsic function in ensuring the survival of virus-specific CD8+ T cells throughout the course of viral infection. We found defective metabolism in Cd38-/- CD8+ T cells arising during chronic infection and changes in their progenitor T cell phenotype. Our studies revealed a dual cell-intrinsic role for CD38 in limiting proliferation and granzyme B production in virus-specific exhausted T cells while also promoting their survival. These data highlight new avenues for research into the mechanisms through which CD38 regulates the survival and metabolism of CD8+ T cell responses to viral infections.

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Exhausted CD8+ T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection.

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Exhausted CD8<sup>+</sup> T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection.

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