TCF1 regulates antiviral T follicular helper (Tfh) cell responses through a negative feedback loop with IL-2 and Blimp1

Th1 cells and T follicular helper cells (Tfh cells), are generated early after viral infection. However, the molecular pathways that drive the differentiation of these two distinct subsets remain unclear. Here, we demonstrate that a molecular circuit involving TCF1, Blimp1, and IL-2 regulates the differentiation of viral-specific Tfh and Th1 cells. Tcf7 gene (encodes TCF1) is actively transcribed in naive and Tfh cells but strongly repressed in Th1 cells. TCF1 expression was negatively correlated with CD25 and Blimp1 expression, and was suppressed by IL2 signaling and Blimp1. Notably, loss of Tcf7 in T cells led to defective Tfh-cell and GC responses after viral infection. Tcf7 -deficient Tfh cells had reduced Tfh transcription signatures and increased Th1 transcription signatures. Moreover, Tcf7 -deficient Tfh cells had lower mitochondrial mass and membrane potential, and showed reduced expression of genes related to oxidative metabolism. Il2ra and Prdm1 (encodes Blimp1) were ectopically expressed in Tcf7 -deficient Tfh cells and were bound by TCF1, suggesting the existence of a negative feedback loop linking TCF1 to IL-2 and Blimp1. Over-expression of Bcl6 rescued Tfh defects caused by Tcf7 deficiency, demonstrating that TCF1 is upstream of the Bcl6-Blimp1 axis. Finally, we found that Tcf7 -deficiency did not cause evident defect in Tfh responses in Th2 immunization models. Therefore, TCF1 specifically regulates antiviral Tfh responses.