T-follicular helper cells survive as long-term memory cells

T-follicular helper (TFH) cells represent the subpopulation of CD4+ T cells that provides help for antigen-specific B cells in the GC response. They are generated from naive T cells during an immune response and are imprinted by their master transcription factor Bcl-6. It has been a long-standing question if TFH cells contribute to the CD4+ memory pool after the GC response has been terminated. To answer this question, we sorted antigen-specific TFH and non-TFH effector cells from an ongoing GC response and transferred them into naive mice. Without further signals via the TCR, transferred cells rapidly contracted with a small population of both TFH and non-TFH cells surviving as memory cells in peripheral lymphoid organs for at least 4 weeks in the absence of antigen. TFH cells strongly downregulated their signature genes Bcl-6, CXCR5, and PD-1 in the memory phase. Upon rechallenge with antigen they rapidly upregulated these markers again. An enhanced potential to produce IL-21, paired with higher expression of CXCR5 and lower expression of CCR7, should enable TFH memory cells to provide more efficient help for antigen-specific B cells than their non-TFH counterparts.