Project Details

Description

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. 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 ?lethargic? phenotype, marked by a deficiency in Tfb1m and depressed mitochondrial biogenesis and defective effector cytokine response. Defective CD8 T cell differentiation was associated also associated with an upregulation of Spry2, a negative regulator of receptor signaling. Induction of defective effector differentiation by helminth coinfection was mediated by host IL-4 and IL-10. To advance mechanistic understanding of helminth induced effector lymphocyte lethargy, we propose three specific aims. In Aim 1, we will leverage our recently developed technical advances and insights to delineate how helminth coinfection negatively impacts CD8 T cell activation, proliferation and differentiation. In Aim2, we will interrogate the functional role of mitochondrial insufficiency in helminth-induced effector dysfunction. Finally, in Aim 3, we will dissect the role of Spry2 and CD8 T cell intrinsic IL4 and IL-10 signaling in helminth-induced lymphocyte lethargy. Together, these studies will advance mechanistic understanding of effector cell dysfunction and provide avenues for therapeutic reversal. !
StatusActive
Effective start/end date5/19/174/30/22

Funding

  • National Institutes of Health: $587,042.00
  • National Institutes of Health: $587,042.00
  • National Institutes of Health: $587,042.00

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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