Person:

Hu, Yu

In chronic infection, T cells become hyporesponsive to antigenic stimulation to prevent immunopathology. Here, we show that TMEM16F is required to curb excessive T cell responses in chronic infection with virus. TMEM16F-deficient T cells are hyperactivated during the early phase of infection, exhibiting increased proliferation and cytokine production. Interestingly, this overactivation ultimately leads to severe T cell exhaustion and the inability of the host to control viral burden. Mechanistically, we identify TMEM16F as the dominant lipid scramblase in T lymphocytes that transports phospholipids across membranes. TMEM16F is located in late endosomes, where it facilitates the generation of multivesicular bodies for TCR degradation and signal termination. Consequently, TMEM16F deficiency results in sustained signaling and augmented T cell activation. Our results demonstrate that scramblase restricts TCR responses to avoid overactivation, ensuring a well-balanced immune response in chronic infectious disease.

CD1a is a lipid-presenting molecule abundantly expressed on Langerhans cells. However, the in vivo role of CD1a remains unclear, principally because CD1a is lacking in mice. Using CD1a-transgenic mice, we show that the plant-derived lipid urushiol triggers CD1a-dependent skin inflammation, driven by CD4+ T cells producing IL-17 and IL-22. Human subjects with poison ivy dermatitis showed a similar cytokine signature following CD1a-mediated urushiol recognition. Among different urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells. We determined the crystal structure of the CD1a-urushiol (C15:2) complex, demonstrating the molecular basis of urushiol interaction with the antigen-binding cleft of CD1a. In a mouse model and psoriasis patients, CD1a amplified inflammatory responses mediated by TH17 cells reactive with self lipid antigens. Treatment with blocking antibodies against CD1a alleviated skin inflammation. Thus, we propose CD1a as a potential therapeutic target in inflammatory skin diseases.