Date Published: May 22, 2017
Publisher: Public Library of Science
Author(s): Som Gowda Nanjappa, Andrew J. McDermott, J. Scott Fites, Kevin Galles, Marcel Wüthrich, George S. Deepe, Bruce S. Klein, Robert A. Cramer.
Our understanding of persistence and plasticity of IL-17A+ memory T cells is clouded by conflicting results in models analyzing T helper 17 cells. We studied memory IL-17A+ CD8+ T-cell (Tc17) homeostasis, persistence and plasticity during fungal vaccine immunity. We report that vaccine-induced memory Tc17 cells persist with high fidelity to the type 17 phenotype. Tc17 cells persisted durably for a year as functional IL-17A+ memory cells without converting to IFNγ+ (Tc1) cells, although they produced multiple type I cytokines in the absence of residual vaccine antigen. Memory Tc17 cells were canonical CD8+ T cells with phenotypic features distinct from Tc1 cells, and were Ror(γ)thi, TCF-1hi, T-betlo and EOMESlo. In investigating the bases of Tc17 persistence, we observed that memory Tc17 cells had much higher levels of basal homeostatic proliferation than did Tc1 cells. Conversely, memory Tc17 cells displayed lower levels of anti-apoptotic molecules Bcl-2 and Bcl-xL than Tc1 cells, yet were resistant to apoptosis. Tc1 cells required Bcl-2 for their survival, but Bcl-2 was dispensable for the maintenance of Tc17 cells. Tc17 and Tc1 cells displayed different requirements for HIF-1α during effector differentiation and sustenance and memory persistence. Thus, antifungal vaccination induces durable and stable memory Tc17 cells with distinct requirements for long-term persistence that distinguish them from memory Tc1 cells.
Memory Th1 and Tc1 (IFNγ+ CD8+ T cells) cells have been well characterized. Following the expansion phase of an immune response, a pool of memory precursor cells (~10%) survives the contraction phase, and slowly differentiates into long-lasting memory cells. Memory Th1 and Tc1 cells are maintained stably for years, often lifelong, even in the absence of cognate antigen [2–4]. Maintenance of memory Th1 and Tc1 is chiefly regulated by IL-7 for survival and IL-15 for intermittent homeostatic turnover[5–7]. Type 1 memory precursors are CD127hi, KLRG-1lo, CD27hi, CD122hi, Bcl-2hi, T-betlo, Eomeshi and TCF-1hi[8,9], and the expression of CD62L and CCR7 distinguish “central memory” vs. “effector memory” T-cell subsets.
The long term persistence and plasticity of Th17 cells varies in different experimental models. The importance of these features carries particular significance in the setting of vaccine immunity where maintenance and fidelity of the phenotype is often required for durable resistance to infection. Here, we studied vaccine-induced Tc17 cells that are essential for resistance against lethal fungal pneumonia in hosts that lack CD4+ T cells. We report that vaccine-induced antifungal memory Tc17 cells are highly durable over a prolonged period of nearly one year in a murine model. The cells stably persist as memory cells, retain the ability to express IL-17A, mediate immunity upon challenge, do not undergo plasticity towards IFNγ (yet do also express other type I cytokines important for fungal immunity), undergo high proliferative renewal, portray phenotypic markers that are consistent with “effector memory” cells, and are dependent on functional HIF-1α for homeostasis but not on Bcl-2 for survival.