Immunity & infection
Exhausted T cells (Tex) are a hallmark of chronic infection and cancer. Blocking inhibitory receptors such as PD-1 reinvigorates Tex, but many patients fail to achieve durable disease control. Thus, deeper understanding of reversal of T cell exhaustion is needed. Little is known about “reprogramming” of Tex into recovered T cells (Trecov) following cure of chronic disease. Here, we aim to determine molecular mechanisms of recovery from exhaustion. To “cure” chronic infection, we adoptively transferred Tex from LCMV-clone13 infected mice into antigen-free mice. Our results reveal recovery of some phenotypic markers of memory T cells (Tmem) and partial recovery from dysfunction, but some “scars” of Tex persisted. For example, CD127/IL-7R expression increased and PD-1 decreased on Trecov, suggesting differentiation toward memory, but frequency of IL-7R+ cells was still lower and PD-1 expression higher when compared to bona fide Tmem. Additionally, single-cell RNAseq indicated that Trecov gene-expression profile resembles Tmem in some respects, but similar to Tex cells in other features. We tested how these changes impacted Trecov recall response, and our challenge experiments revealed that although Trecov recall capacity was better than Tex, it was still inferior to Tmem on a per cell basis. We are currently investigating whether the transcriptional and functional scars have epigenetic roots. Together, these results suggest that following elimination of persistent antigenic stimulation previously-exhausted T cells recover some Tmem properties, while other aspects remain “scarred” from their exhaustion history. These studies will enhance our understanding of mechanisms of Tex recovery, and identify novel immunotherapeutic strategies.