Cytotoxic CD4 T cells control host immunity during viral persistence

Abstract

Abstract The CD4 T helper cell lineage is initially established and controlled in the thymus by the transcription factor, ThPOK. Sustained expression of ThPOK by mature T cells in the periphery maintains the CD4 T helper commitment and allows for plasticity and differentiation to different helper fates (Th1, Th2, Th17...) in response to stimulation with cognate antigens. Our group demonstrated before that in the intestine, repeated stimulation of mature CD4 T cells results in the loss of ThPOK expression followed by the reprogramming of the T helper cells to CD4 cytotoxic T lymphocytes (CTL), expressing notably CD8 T cells attributes (such as Runx3, granzyme B). Continuous activation is also characteristic of chronic viral infections. We therefore investigated if viral infections lead to the generation of reprogrammed CD4 CTL and moreover if these reprogrammed CD4 CTL play essential roles for the organism’s protection. Using the well-defined lymphocytic choriomeningitis virus (LCMV) acute (strain LCMV-Amstrong) versus chronic (LCMV-Clone 13) infection model, we observed that solely chronic infection enables activated CD4 T helper cells to lose ThPOK and convert to CTL with potent killer activity. Moreover, viral-induced CD4 CTL precursors produce various cytokines, notably Il-10, which is required for the induction of the reprogramming process. Finally, we engineered two unique mouse model systems, in which either all the CD4 T cells are forced to reprogram to CTL (gain of function) or else, prevented from reprogramming to CTL (loss of function). Using these models, we show that the reprogrammed CD4 CTL generated under chronic infection conditions, play critical roles in protective immunity.