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

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.

Calnexin Induces Expansion of Antigen-Specific CD4+ T Cells that Confer Immunity to Fungal Ascomycetes via Conserved Epitopes

“…After vaccination with calnexin, 15-20% of the tetramer-positive cells in the draining lymph nodes display the chemokine receptors CCR6 or CXCR3 (Fig. S5B) , which are respectively linked with Th17 and Th1 cell recruitment (Hirota et al, 2007; Nanjappa et al, 2012a; Nanjappa et al, 2012b). Nearly 30% of tetramer-positive cells recruited to the lung were IL-17 producers in calnexin-vaccinated mice (Fig 4C) .…”

“…We previously demonstrated that IL-17 production by CD4 + T cells is indispensable in vaccine immunity against dimorphic fungi that cause North American systemic mycoses ((Nanjappa et al, 2012a; Wüthrich et al, 2011a). We have found that IL-17 producing T cells are maintained and persist after vaccination with attenuated yeast in CD4-sufficient and -deficient mice (Nanjappa et al, 2012a; Wüthrich et al, 2011a). In contrast, others have reported that IL-17 producing T cells are short lived and dwindle due to death or conversion to type 1 cytokine producing T cells (Hirota et al, 2011; Pepper et al, 2010).…”

Interferon regulatory factor 3 controls interleukin-17 expression in CD8 T lymphocytes

“…A physiological role for Tc17 cells is emerging. These cells are critical for immunity against invading fungi in immune-deficient hosts and protect against lethal influenza infection in mouse and humans (23,24). In mouse models of lymphocytic choriomeningitis virus (LCMV), CD8 T cells lacking T-bet and eomesodermin massively differentiated into Tc17, leading to live-threatening multiorgan infiltration of neutrophils (25).…”

Interleukin-1 Receptor but Not Toll-Like Receptor 2 Is Essential for MyD88-Dependent Th17 Immunity to Coccidioides Infection

“…Control mice received equivalent amounts of normal rat IgG (Sigma Chemical Co.). The efficacy of neutrophil depletion in lungs was monitored with monoclonal antibodies against CD11b and LFA1 in a flow cytometry assay as previously described (27).…”