Genesis of Defective Effector Lymphocytes in the Helminth-Coinfected Host

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 DESCRIPTION (provided by applicant): Abstract: Helminth infections occur in populations worldwide and potentially modulate the immune response to unrelated pathogens. An important consideration in the field is that concomitant helminth infection could decrease the efficacy of vaccines. How helminth infection modulates type 1 immunity is unclear. Previously studies have suggested a regulatory role for helminth products, changes in host microbiota and direct immunoregulation of T cell activation by the Th2 dominated immune response. It is not known how helminth infection impacts the formation and function of effector cells. Using an ecologically appropriate model of mouse coinfection with H. polygyrus and vaccination with T. gondii, we find that helminth infection inhibited the differentiation of effector CD8 T cells. Furthermore, the effector CTLs that develop in coinfected mice exhibit an intrinsic functional defect, marked by a deficiency in Tfb1m and upregulation of Spry2. Defective CD8 T cell differentiation was associated with an inhibition of the CD8+ DC mediated IL-12 response, which was relieved by STAT6 deficiency. However, the absence of STAT6 alone was not sufficient to rescue defective effector differentiation. Instead, combined blockade of IL-4 and IL-10 was required for restoration of CD8 T cell differentiation. To explain the dual requirement for IL4 and IL- 10, we propose the hypothesis that helminth infection induces these two cytokines to inhibit multiple points in the innate and adaptive immune tissue environments where the activation, proliferation and differentiation of effector CD8 T cells occur. We propose three specific aims to advance our mechanistic understanding of helminth immunomodulation of effector lymphocyte generation. In Aim 1, we will use newly developed analytical methods and a novel paradigm for extrafollicular generation of effector CD8 T cells to track which critical checkpoints are affected by helminth coinfection. In Aim 2, we focus on defining how CD8 T effector cells become intrinsically defective, particularly focusing on the roles of Spry2 and Tfb1m in altered signaling and defective mitochondrial biogenesis andmetabolism. Finally, in Aim 3, we will interrogate the cell intrinsic role of IL4 and IL-10 signaling in T cells versus other innate and adaptive immune cells in mediating helminth immunoregulation. We will also integrate and validate our general hypothesis that robust immunomodulation of type 1 adaptive immunity by helminth coinfection is based on the combined inhibitory effects of IL4 and IL-10 on distinct innate components.