Antigen-dependent multistep differentiation of T-follicular helper cells and its role in SARS-CoV-2 infection and vaccination

T-follicular helper (Tfh) cells play an essential role in regulating the GC reaction and, consequently, the generation of high-affinity antibodies and memory B cells. Therefore, Tfh cells are critical for potent humoral immune responses against various pathogens and their dysregulation has been linked to autoimmunity and cancer. Tfh cell differentiation is a multistep process, in which cognate interactions with different APC types, costimulatory and coinhibitory pathways, as well as cytokines are involved. However, it is still not fully understood how a subset of activated CD4(+) T cells begins to express the Tfh-defining chemokine receptor CXCR5 during the early stage of the immune response, how some CXCR5(+) pre-Tfh cells enter the B-cell follicles and mature further into GC Tfh cells, and how Tfh cells are maintained in the memory compartment. In this review, we discuss recent advances on how cognate interactions and antigen are important for Tfh cell differentiation and long-term persistence of Tfh cell memory, and how this is relevant to the current understanding of COVID-19 pathogenesis and the development of potent SARS-CoV-2 vaccines.

Automated summary

Tfh cells are essential for potent humoral immune responses, and their differentiation and memory maintenance are influenced by various factors, including interactions with APCs, costimulatory and coinhibitory pathways, and cytokines. Understanding the differentiation and memory maintenance of Tfh cells is crucial for a deeper understanding of immune responses and vaccine development.