Stepwise Tfh cell differentiation revisited: new advances and long-standing questions

T follicular helper (Tfh) cells play an essential role in germinal center formation and the generation of high-affinity antibodies. Studies have proposed that Tfh cell differentiation is a multi-step process. However, it is still not fully understood how a subset of activated CD4⁺ T cells begin to express CXCR5 during the early stage of the response and, shortly after, how some CXCR5⁺ precursor Tfh (pre-Tfh) cells enter B cell follicles and differentiate further into germinal center Tfh (GC-Tfh) cells while others have a different fate. In this mini-review, we summarize the recent advances surrounding these two aspects of Tfh cell differentiation and discuss related long-standing questions, including Tfh memory.