Anti-Fungal Functional Tc17 Cells Persist as Long-Lasting Memory Without Plasticity Towards IFNγ

Abstract

Abstract Memory homeostasis of Th1/Tc1 cells is well characterized, whereas memory Th17-cell homeostasis, persistence and plasticity are debated. We have shown that IL-17A-producing CD8+ T-cells (Tc17) are necessary for vaccine-induced fungal immunity in CD4+ T-cell compromised hosts. Here, we systematically evaluated persistence, fidelity, plasticity and functional role in immunity of anti-fungal Tc17 cells using IL-17A fate-mapping reporter mice. We show that Tc17 cells stably maintained as functional bona fide IL-17A producing memory cells, with little plasticity towards IFNγ, even in the absence of vaccine antigen. Memory Tc17 cells stably and progressively improved in their production of multiple Tc1 cytokines but not IFNγ, and contributed for IL-17A-dependent vaccine resistance. Memory Tc17 cells were canonical CD8+ T cells portraying a set of phenotypic attributes that were distinct from Tc1 cells while remaining Ror(γ)hi, T-betlo and EOMESlo. Interestingly, in contrast to Tc1, memory Tc17 cells expressed lower levels of anti-apoptotic factors Bcl-1, Bcl-xL and MCL-1. However, basal homeostatic proliferation of memory Tc17 cells was significantly higher than Tc1 cells. Finally, we unraveled a dichotomous role of HIF-1α for effector vs memory Tc1 and Tc17 cells, where HIF-1α was essential for expression of IL-17A in memory cells while it was required for expression of IFNγ in effector cells.