PD-1+ Tcf1+ CD8+ T cells from established chronic infections can convert into memory cells but keep a stable imprint of persistent stimulation

The CD8+ T cell response to chronic viral infection is sustained by virus-specific memory-like (TML) CD8+ T cells. TML have recall expansion, self-renewal and differentiation capacity, similar to central memory (TCM) CD8+ T cells that arise in response to acute infection and persist long-term in the absence of antigen. An unresolved question is whether TML can also form memory. Here we showed that TML persisted in antigen free hosts. Further, in response to acute restimulation, TML expanded and differentiated inefficiently, but self-renewal and long-term persistence was not very different from TCM. Progeny of TML resembled conventional memory cells but retained multiple characteristics of chronically stimulated cells. This imprint was accounted for by the overexpression of the transcription factor Tox. Our findings demonstrated that chronically stimulated CD8+ T cells yielded memory that, however, differed from conventional memory formed in response to acute resolved infection. B6 mice (CD45.1/.2) and TCR Vb5 transgenic mice (CD45.1) were transferred with Tcf7GFP P14 cells from naive mice (CD45.2) and infected with LCMV Armstrong (Arm) and LCMV clone 13 (cl13), respectively. Total P14 cells were flow sorted at d32 post infection. Alternatively, Tcf7GFP+ P14 cells were flow sorted at d45 post Arm and cl13 infection and transferred into secondary B6 mice (CD45.1/.2) that were infected with LCMV Arm. Total P14 cells were flow sorted at d42 post infection (Tcm>Arm) and (Tml>Arm). Each sample derived from a pool of at least 3 mice.