PD-1⁺ Tcf1⁺ CD8⁺ T cells from established chronic infection can form memory while retaining a stableimprint of persistent antigen exposure.

Abstract

Virus-specific PD1 <sup>+</sup> Tcf1 <sup>+</sup> memory-like CD8 <sup>+</sup> T cells (T <sub>ML</sub> s) maintain the CD8 <sup>+</sup> T cell response during chronic viral infection. However, the fate of these cells following cessation of persistent antigen exposure has been unclear. Here, we find that T <sub>ML</sub> s persist upon transfer into antigen-free hosts and form memory following recall stimulation. Phenotypic, functional, and transcriptome analyses show that T <sub>ML</sub> -derived memory cells resemble those arising in response to acute, resolved infection, but they retain features of chronically stimulated cells, including elevated PD-1 and Tox and reduced cytokine expression. This chronic infection imprint is largely accounted for by constitutive Tox expression. Virus-specific Tcf1 <sup>+</sup> CD8 <sup>+</sup> T cells that persist after clearance of systemic infection also display a chronic infection imprint. Notwithstanding, renewed virus exposure induces a recall response, which controls virus infection in part. Thus, cessation of chronic antigen exposure yields a memory CD8 <sup>+</sup> T cell compartment that reflects prior stimulation