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. !
Helminth coinfection alters disease progression and the immune response to unrelated pathogens and antigens. We have developed a new model to explain how helminth infection exerts immunomodulation of effector lymphocytes. The studies proposed will dissect the precise steps in effector lymphocyte development affected by helminths. The role of mitochondrial dysfunction and host cytokines in negatively impacting effector T cell function will be investigated. These studies should provide validated markers for identification of defective T cells developing in humans coinfected with helminthes and pinpoint strategies for reversal of helminth immunomodulation. !
|Yap, George S; Gause, William C (2018) Helminth Infections Induce Tissue Tolerance Mitigating Immunopathology but Enhancing Microbial Pathogen Susceptibility. Front Immunol 9:2135|
|Lau, Colleen M; Tiniakou, Ioanna; Perez, Oriana A et al. (2018) Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells. J Exp Med 215:2265-2278|