Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation

Abstract

Exhausted CD8 T cells (T EX ) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies like PD-1 blockade can re-invigorate T EX cells, but re-invigoration is not durable. A major unanswered question is whether T EX cells differentiate into functional durable memory T cells (T MEM ) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, T EX cells partially (re)acquire phenotypic and transcriptional features of T MEM cells. These “recovering” T EX cells originated from the T-cell factor (TCF-1 + ) T EX progenitor subset. Nevertheless, the recall capacity of these recovering-T EX cells remained compromised compared to T MEM cells. Chromatin-accessibility profiling revealed failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for T EX cell targeted immunotherapies.

Towards a Systems Immunology Approach to Understanding Correlates of Protective Immunity against HCV

“…Interestingly, one study in a chimpanzee treated with DAA then experimentally rechallenged demonstrated that pre-existing intrahepatic HCV-specific CD8+ T cells were narrowly focused and failed to prevent viral persistence [ 93 ]. Both the transcriptomic and epigenetic profiles observed in HCV-infected subjects were recapitulated in another study in the LCMV model, thus underscoring common exhaustion molecular mechanisms in different infection models [ 92 ]. Experiments in the LCMV mouse model demonstrated that recovered exhausted CD8+ T cells adoptively transferred into naïve mice and rechallenged with the virus possessed inferior recall capacity as compared to conventional memory T cells, which is only partially improved with PD-L1 blockade [ 92 ].…”

“…Both the transcriptomic and epigenetic profiles observed in HCV-infected subjects were recapitulated in another study in the LCMV model, thus underscoring common exhaustion molecular mechanisms in different infection models [ 92 ]. Experiments in the LCMV mouse model demonstrated that recovered exhausted CD8+ T cells adoptively transferred into naïve mice and rechallenged with the virus possessed inferior recall capacity as compared to conventional memory T cells, which is only partially improved with PD-L1 blockade [ 92 ]. New studies examining the immune response and reversal of exhaustion following reinfection in DAA-treated subjects will be essential to validate these findings in human HCV infections.…”

“…CD127 hi cells and CD127 lo cells had the molecular and phenotypic signatures of memory-like and exhausted CD8+ T cells, respectively [ 89 ]. These memory-like and exhausted signatures were shared with CD8+ T cells in the LCMV mouse model and cancer [ 89 , 90 , 92 ]. scRNA-seq together with T cell receptor typing identified a progenitor–progeny relationship between CD127 hi memory-like and CD127 lo exhausted CD8+ T cells via a CD127 int intermediate stage [ 89 ].…”

“…They identified a core regulatory program in exhausted HCV-specific CD8+ T cells. This epigenetic program was conserved across other chronic viral infections such as human immunodeficiency virus (HIV) and LCMV [ 91 , 92 ]. Furthermore, this program was largely irreversible for up to 80 weeks following DAA-mediated clearance, suggesting that exhausted HCV-specific T cells were locked into a permanent dysfunctional state [ 91 ].…”

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

“…Similar to the case of cancer cells, the aforementioned metabolic aberrations also contribute to the epigenetic reprogramming of immune cells. Notably, these heritable and long-lasting changes can cause a chronic exhaustion phenotype in effector cells, which might not simply be reverted by immune checkpoint blockade alone, leading to the development of nonresponsiveness [103,104]. Here, we highlight the epigenetic changes of immune cells under the context of tumor-induced metabolic reprogramming.…”