TOX and PD-1 are required for the maintenance of CD4 T cell precursors during chronic infection

In contrast with the well-established mechanisms that maintain exhausted CD8 T cells, our knowledge about the differentiation and in particular the molecular control of CD4 T cells in chronic infections is limited. Using the lymphocytic choriomeningitis virus (LCMV) infection model, we identified that CXCR5 + TCF-1 + CD4 T cells, found mainly in secondary lymphoid organs, serve as precursors for the CD4 population. These cells transition into terminally differentiated cells and combine T follicular helper (T FH ) cell features (IL-21 expression) with T helper 1 (T H 1) cell characteristics (CXCR6 expression and IFN-γ and TNF secretion). In the CXCR5 + TCF-1 + population, CD62L + cells exhibit the highest re-expansion potential in adoptive transfer settings. All subsets express TOX and PD-1, which ensure the maintenance of the CD4 T cell population. Absence of either factor reduces the number of CD62L + precursors and impairs their further differentiation. Overall, we define a hierarchical framework for CD4 T cell maintenance in chronic infection and reveal common mechanisms that sustain both exhausted CD4 and CD8 T cell responses.