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Gfi1 controls the formation of effector CD8+ T cells during chronic infection and cancer [RNA]

ABSTRACT: During chronic infection and tumor progression, CD8+ T cells gradually lose their cytotoxic effector function and become “exhausted”. These “exhausted” CD8+ T cells are highly heterogenous and comprised of various subsets, including a self-renewing progenitor subset that gives rise to Ly108-CX3CR1+ effector cells with some cytotoxic capabilities. Generation of these effectors is essential for the control (although limited) of chronic infection and tumor. However, the precise cues and mechanisms directing their formation and maintenance remains incompletely understood. In this study, using genetic mouse models challenged with the LCMV clone 13 infection and syngeneic MB49 urothelial adenocarcinoma, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in “exhausted” CD8+ T cells. By controlling chromatin accessibility and transcriptomic programs, Gfi1 governs the generation of the effector cells. Deletion of Gfi1 in T cells arrests the progenies from progenitors in a Ly108+CX3CR1+ Transitional state, without further differentiation into effector cells. Given the programmable chromatin profile of these transitional cells, we reason that they are a better target than the highly irreprogrammable terminally differentiated cells for therapeutic interventions to combat chronic infection and cancer. Our results show that Gfi1 is a novel epigenetic and transcriptional regulator of CD8+ T cell exhaustion.

ORGANISM(S): Mus musculus

PROVIDER: GSE261249 | GEO | 2025/04/10

REPOSITORIES: GEO

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Gfi1 controls the formation of effector CD8+ T cells during chronic infection and cancer [ATAC]

Project description:During chronic infection and tumor progression, CD8+ T cells gradually lose their cytotoxic effector function and become “exhausted”. These “exhausted” CD8+ T cells are highly heterogenous and comprised of various subsets, including a self-renewing progenitor subset that gives rise to Ly108-CX3CR1+ effector cells with some cytotoxic capabilities. Generation of these effectors is essential for the control (although limited) of chronic infection and tumor. However, the precise cues and mechanisms directing their formation and maintenance remains incompletely understood. In this study, using genetic mouse models challenged with the LCMV clone 13 infection and syngeneic MB49 urothelial adenocarcinoma, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in “exhausted” CD8+ T cells. By controlling chromatin accessibility and transcriptomic programs, Gfi1 governs the generation of the effector cells. Deletion of Gfi1 in T cells arrests the progenies from progenitors in a Ly108+CX3CR1+ Transitional state, without further differentiation into effector cells. Given the programmable chromatin profile of these transitional cells, we reason that they are a better target than the highly irreprogrammable terminally differentiated cells for therapeutic interventions to combat chronic infection and cancer. Our results show that Gfi1 is a novel epigenetic and transcriptional regulator of CD8+ T cell exhaustion.

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2016-06-10 | E-GEOD-63118 | biostudies-arrayexpress

CX3CR1/Fractalkine receptor expression separates memory CD8+ T cells with distinct functional profiles (RNA-seq)

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Project description:CD8+ T cells play a critical role in the immune response to viral pathogens. Persistent human CMV (HCMV) infection results in a strong increase in the number of virus-specific, quiescent effector-type CD8+ T cells with constitutive cytolytic activity, but the molecular pathways involved in the induction and maintenance of these cells are unknown. We show here that HCMV infection induced acute and lasting changes in the transcriptomes of virus-reactive T cells collected from HCMV-seropositive patients at distinct stages of infection. Enhanced cell cycle and metabolic activity was restricted to the acute phase of the response, but at all stages, HCMV-specific CD8+ T cells expressed the Th1-associated transcription factors T-bet (TBX21) and eomesodermin (EOMES), in parallel with continuous expression of IFNG mRNA and IFN-g–regulated genes. The cytolytic proteins granzyme B and perforin as well as the fractalkine-binding chemokine receptor CX3CR1 were found in virus-reactive cells throughout the response. During HCMV latency, virus-specific CD8+ T cells lacked the typical features of exhausted cells found in other chronic infections. Persistent effector cell traits together with the permanent changes in chemokine receptor usage of virus-specific, nonexhausted, long-lived CD8+ T cells may be crucial to maintain lifelong protection from HCMV reactivation. CD8+ T cells of naive, effector, and memory type were isolated from six latently chronic-infected healthy donors. For RNA isolation and microarray analysis, 3 independent donors and a pool of 3 additional healthy individuals were used. Total RNA of all naive CD8+ T cells was pooled and used as a common reference sample.

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