This R01 renewal addresses the role and action of IL-17 producing CD8+ T cells (Tc17 cells) that mediate vaccine immunity against lethal fungal pneumonia in CD4+ T-cell deficient hosts. In a model of pulmonary blastomycosis in mice lacking CD4+ T cells (mimics AIDS or CD4+ T cell lymphopenia), vaccination prevents death and reduces the lung yeast burden by up to 6 logs; Tc17 cells play a major role in this resistance. We made several unexpected and significant findings in this model during the last funding period that form the basis of this renewal. First, whereas CD8+ T cells raised without CD4+ help against bacteria and viruses fail to acquire long-term memory, we found that anti-fungal CD8+ T cells induced in CD4+ deficient hosts do acquire long-term memory, and that they persist for an extended period and confer resistance. Second, while type 1 cytokine producing CD8+ T cells contribute to vaccine immunity, they are dispensable, yet Tc17 cells are obligate and indispensable. Third, intrinsic MyD88 signals in the CD8+ T cell itself induce the development of antigen specific, anti-fungal Tc17 cells. Our goal is to delineate the mechanisms that regulate Tc17 differentiation and promote their long-term survival after fungal vaccination of CD4+ T cell deficient hosts. We postulate that MyD88 signals intrinsically regulate Tc17 differentiation by PI-3 kinase-Akt pro-survival signals in CD8+ T cells; that TLR2 activation by yeast surface mannan drives this intrinsic signaling pathway; and that persistence of Tc17 cells, or re- differentiation upon antigen re-challenge, is swayed by these signals.
Our aims are to: 1. Define the role and mechanism of MyD88 in intrinsic control of development of anti-fungal Tc17 cells. By using mice to conditionally delete (with tamoxifen) MyD88 in only T cells, we will study when & how MyD88 intrinsically directs Tc17 cell development, and dissect the role of PI-3 kinase-Akt pro-survival signals in CD8+ cells. 2. Identify the TLR on CD8+ T cells and ligand on vaccine yeast that induce development of anti-fungal Tc17 cells. We will extend preliminary data showing that TLR2 ligation by yeast surface mannan induces proliferation and survival signals via PI-3K and Akt signaling. Oligosaccharides identified will be investigated as Tc17 adjuvants. 3. Dissect the role of MyD88 during the memory phases of anti-fungal Tc17 cell-mediated vaccine immunity. We will track the long-term fate of Tc17 cells using novel fate reporter mice, interrogate their role in resistance, and clarify the influence of MyD88 on maintenance or recall and Tc17 re-differentiation during memory. Our work tackles an unmet need: developing and understanding vaccines against fungi. It breaks new ground about anti-fungal memory immunity in CD4 deficient hosts, the role of Tc17 cells, and how these cells develop and their developmental pathways can be harnessed by adjuvant to protect immune deficient patients.
Systemic fungal infections represent a significant and growing public health problem. In the United States, invasive fungal infections are now one of the 10 leading causes of death (7th) even ahead of mortality due to tuberculosis. Our work tackles the significant unmet need of developing vaccines against fungal pathogens that cause disease in humans.
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