Divergent CD8 memory T cell subsets in an encephalitis model of Toxoplasma gondii infection

Toxoplasma gondii is a foodborne pathogen with important human implications. Polyfunctional CD8 T cell immunity is critical for keeping the chronic infection under control. However, in susceptible animals, T-cell exhaustion leads to the reactivation of the infection. Phenotypic and transcriptomic analyses of the polyclonal antigen-specific CD8 T cell response in these mice define four different subsets based on KLRG1 and CD62L expression. While pop1 (KLRG1+CD62Llo) bears the characteristics of a terminal effector population, pop3 (KLRG1-CD62Lhi) resembles stem-like CD8 T cells described in other models and can transition into pop1 either directly or via pop2 (KLRG1-CD62Llo) and pop4 (KLRG1+CD62Lhi). Interestingly, despite sharing several surface markers and being derived from pop3, intermediate effector/memory pop4 exhibits strong genetic similarities with pop1 with only a 43 differentially expressed genes divergence between the two populations. Although all memory subsets (pop2-4) display elevated inhibitory receptors, pop4 also exhibits increased levels of costimulatory molecules. Therefore, this subset maintains its functional fitness even during the late chronic infection when other subsets including pop1 become dysfunctional. Overall, our studies demonstrate that stem-like memory CD8 T cells (pop3) develop early after infection when the pop1 effector subset is still functional. Significantly, pop3 gives rise to an exhausted dysfunctional pop2 but more importantly, is a source of highly functional pop4. However, despite the generation of a complex CD8 T cell response, the susceptible host is ultimately unable to contain T. gondii and prevent encephalitis.