Large neutral amino acid uptake and mTOR activation within CD4 T cells coordinate type 2 immunity and host resistance...

Trichuris trichiura (whipworm) is a gastrointestinal nematode that infects approximately 465 million people worldwide. Trichuris 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 CD4Th2 response and interleukin (IL-)13 production. T cells up-regulate glycolysis and uptake of substrates following activation. The amino acid transporter SLC7A5 has been shown to be necessary for activation of mTORC1, a nutrient/energy/redox sensor critical for T cell differentiation into effector cells.

We found that mice lacking SLC7A5 in CD4T cells have significantly delayed worm expulsion, associated with reduced IL-13, reduced pmTOR, and reduced glycolytic rates. However, as infection progressed, IL-13 levels recovered in T cell-specific SLC7A5-deficient mice, alongside resistance. The critical role of CD4T cell metabolism per se and downstream mTOR in CD4T cells in host resistance was shown in mice lacking mTOR in CD4T cells that failed to expel their parasites and developed chronic infection.

Our study shows that mTOR is essential for optimal functioning of T cells during whipworm infection and that deletion of Slc7a5 significantly delays worm clearance indicating a key role for amino acid acquisition by CD4T cells in resistance to helminth infection.