Large Neutral Amino acid uptake and mTOR activation within CD4+ T cells coordinate Type 2 immunity and host resistance to Trichuris muris

Abstract

Trichuris trichiura (whipworm) is a gastrointestinal nematode that infects approximately 465 million people worldwide. T. muris is used as a tractable model for the human whipworm. In wild type mice, infection with a high dose of T. muris eggs leads to worm expulsion, which is dependent on a CD4+Th2 response and interleukin (IL-)13 production. It is known that T cells up-regulate glycolysis and uptake of substrates upon activation. The amino acid transporter SLC7A5 has been shown necessary for activation of mTORC1, a nutrient/energy/redox sensor critical for T cell differentiation into effector cells. We found that at the peak of the immune response to T. muris, mice lacking SLC7A5 in CD4+T cells have delayed worm expulsion, lower levels of IL-13, reduced pmTOR and glycolytic rates. However, at later stages of infection IL-13 levels partially recovered alongside resistance. The critical role of CD4+T cell metabolism per se and down-stream mTOR in CD4+T cells in resistance was shown in mice lacking mTOR in CD4+T cells, that failed to expel a high dose of parasites and developed chronic infection. Our study shows that mTOR is essential for effective functioning of T cells during whipworm infection and that deletion of Slc7a5 significantly delays worm clearance.