Tc17 Cells Mediate Vaccine Immunity against Lethal Fungal Pneumonia in Immune Deficient Hosts Lacking CD4+ T Cells

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Abstract
Vaccines may help reduce the growing incidence of fungal infections in immune-suppressed patients. We have found that, even in the absence of CD4+ T-cell help, vaccine-induced CD8+ T cells persist and confer resistance against Blastomyces dermatitidis and Histoplasma capsulatum. Type 1 cytokines contribute to that resistance, but they also are dispensable. Although the role of T helper 17 cells in immunity to fungi is debated, IL-17 producing CD8+ T cells (Tc17 cells) have not been investigated. Here, we show that Tc17 cells are indispensable in antifungal vaccine immunity in hosts lacking CD4+ T cells. Tc17 cells are induced upon vaccination, recruited to the lung on pulmonary infection, and act non-redundantly in mediating protection in a manner that requires neutrophils. Tc17 cells did not influence type I immunity, nor did the lack of IL-12 signaling augment Tc17 cells, indicating a distinct lineage and function. IL-6 was required for Tc17 differentiation and immunity, but IL-1R1 and Dectin-1 signaling was unexpectedly dispensable. Tc17 cells expressed surface CXCR3 and CCR6, but only the latter was essential in recruitment to the lung. Although IL-17 producing T cells are believed to be short-lived, effector Tc17 cells expressed low levels of KLRG1 and high levels of the transcription factor TCF-1, predicting their long-term survival and stem-cell like behavior. Our work has implications for designing vaccines against fungal infections in immune suppressed patients. Systemic fungal infections have emerged as a public health problem, especially for patients with suppressed immunity. At present, there are no vaccines against fungi, partly because it is hard to elicit strong immunity in immune suppressed patients. We have found however that residual elements of T cell immunity can be harnessed by vaccination even in immune suppressed hosts. We show here that immune suppressed mice lacking T helper cells can still be vaccinated successfully against lethal fungal pneumonia. A population of T cytotoxic IL-17-producing cells (Tc17 cells) is instrumental and indispensible in vaccine protection. We describe here mechanisms that explain how these cells are induced to mature in Tc17 cells, persist for long periods in the body providing “immune memory”, recruit to the site of infection, and clear the tissue of fungi. Our work sheds new light on potent T cells that can be harnessed by vaccine strategies against fungal infection in vulnerable patients.

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