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"Mechanisms of Inhibition of CD8+ T Cell Immunity During Helminth Infection"

Andrew Marple
M.D./Ph.D. Program
B.S. 2006, University of Maryland

Thesis Advisor: George Yap, Ph.D.
Associate Professor
Department of Medicine- Center for Immunity and Inflammation

Monday, May 13, 2013
9:00 A.M., MSB B610


Upon infection, the protozoan parasite Toxoplasma gondii induces a strongly polarized Th1 cytokine response, necessary for effector differentiation of CD8 lymphocytes. Pre-infection with an intestinal nematode, such as Heligmosomoides polygyrus has been shown to attenuate immune responses to intracellular pathogens and inhibit the development of Th1 responses. Previous studies have shown that mice co-infected with H. polygyrus and T. gondii exhibit suppressed CD8+ T cell responses against T. gondii, yet the precise mechanism by which co-infection impinges upon the priming and differentiation of antigen-specific T cells remains to be determined. Using a novel Kb-peptide tetramer-binding assay for tgd057-reactive CD8+ T cells, we show that co-infected mice develop a diminished antigen-specific response to T. gondii. Co-infected mice developed fewer antigen-specific CD8+ T cells, a decreased fraction of terminally differentiated effector cells, and reduced effector IFN- production. Terminally differentiated antigen-specific effector T cells (CD62Llo, KLRG1+) from co-infected mice retained an intrinsic defect in cytokine production, which is putatively associated with the expression of Spry2, an inhibitor of receptor tyrosine kinase signaling. While tgd057-specific CD8+ T cell differentiation and effector function remained inhibited in co-infected STAT6-/- and IL-10-/- mice, helminth-induced inhibition of differentiation and effector function was abrogated in co-infected IL-4/IL-10-/- mice, thus indicating the ability of either cytokine to mediate suppression of CD8+ T cell effector responses during helminth infection.

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