To study the impact of antigen loss on exhausted T cells (TEX), Abdel-Hakeel et al. used adoptive transfer of LCMV-specific TEX and memory T cells into infection-free and previously immune mice to examine proliferation, phenotype, and gene transcription patterns. In the absence of antigen, TEX were more poorly maintained and exhibited a partial shift toward a less exhausted phenotype, with a transcription profile characterized by lower expression of some exhaustion markers (PD-1, TOX), but not others, and a lower functional capacity to respond to infection. Epigenetically, these recovered T cells retained most open chromatin regions characteristic of TEX.
Contributed by Ed Fritsch
This paper was co-submitted along with these 2 others:
Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
ABSTRACT: Exhausted CD8 T cells (TEX) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate TEX cells, but reinvigoration is not durable. A major unanswered question is whether TEX cells differentiate into functional durable memory T cells (TMEM) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, TEX cells partially (re)acquire phenotypic and transcriptional features of TMEM cells. These 'recovering' TEX cells originated from the T cell factor (TCF-1+) TEX progenitor subset. Nevertheless, the recall capacity of these recovering TEX cells remained compromised as compared to TMEM cells. Chromatin-accessibility profiling revealed a 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 TEX cell-targeted immunotherapies.
Author Info: (1) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. (2) Institute for Immunology, Perelman School of Medicine,
Author Info: (1) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. (2) Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. (4) Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Microbiology and Immunology, University of Miami, Miami, FL, USA. (6) Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. (7) Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. (8) Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA. (9) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu. (10) Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu. (11) Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.
