Role for Blimp-1 in the generation and function of cytotoxic CD4 effector T cells identified by NKG2A/C/E expression (P6046)

Abstract

Abstract CD4 T cells are best known for helper roles in immunity, but they can also acquire cytotoxic activity (ThCTL) and kill MHC class II+ targets presenting cognate antigen. We have identified a subset of CD4 effectors in the lung of influenza A/PR8 (IAV)-infected mice that peak at 8 days post-infection. They mediate potent perforin-dependent, Fas-independent antigen-specific cytotoxic activity and express the NK cell-associated receptors NKG2A/C/E. CD4 T cells from lung, spleen and draining lymph nodes express mRNA for the NKG2A inhibitory receptor, while mRNA for the activating receptors, NKG2C and NKG2E, are only detected in the lung. Interestingly, blocking NKG2A/C/E receptors or their ligand, non-classical MHC class I molecule Qa-1, significantly inhibits ThCTL-mediated specific killing of target cells. The NKG2A/C/E+ ThCTL subset co-expresses PD-1, CD27, PSGL-1 and Ly6c, but not CD103, as well as transcription factors Blimp-1 and Eomes. We analyzed the role of transcriptional repressor Blimp-1 in the CD4 response and found that although the conditional KO of Blimp-1 in T cells did not affect total numbers of CD4 effectors in IAV-infected lung, it significantly reduced the number of ThCTL, their expression of the aforementioned phenotype and their cytotolytic function. NKG2A/C/E is a valuable marker for identifying ThCTL that are generated during an acute anti-viral response through a unique program that involves Blimp-1.