The development and fate of follicular helper T cells defined by an IL-21 reporter mouse

Germinal centers require CD4(+) follicular helper T cells (T-FH cells), whose hallmark is expression of the transcriptional repressor Bcl-6, the chemokine receptor CXCR5 and interleukin 21 (IL-21). To track the development and fate of T-FH cells, we generated an IL-21 reporter mouse by introducing sequence encoding green fluorescent protein (GFP) into the Il21 locus; these mice had expression of IL-21-GFP in CD4(+)CXCR5(+)PD-1(+)T(FH) cells. IL-21-GFP(+) T-FH cells were multifunctional helper cells that coexpressed several cytokines, including interferon-gamma (IFN-gamma), IL-2 and IL-4. T-FH cells proliferated and gave rise to transferrable memory cells with plasticity, which differentiated after recall into conventional effector helper T cells and T-FH cells. Thus, we demonstrated that T-FH cells were not terminally differentiated but instead retained the flexibility to be recruited into other helper T cell subsets and nonlymphoid tissues.