Memory Phenotype Tfh Cells Develop Without Overt Infection and Support Germinal Center Formation and B Cell Responses to Viral Infection

Pathogen-induced memory Tfh cells are important to maintain high-affinity antibodies against pathogens. We have now discovered Tfh cells with a similar memory phenotype (MP) that develop in pathogen-free conditions. These MP Tfh cells are similar to pathogen-induced memory Tfh in both phenotype and function. They express FR4 and Egr2, which are both found in pathogen-induced memory Tfh cells. FR4⁺Egr2⁺ CD4 MP cells express genes involved in the development of Tfh cells and homeostatic proliferation, as well as key metabolic pathways discovered in pathogen-induced memory Tfh cells. MP Tfh cells can support B cell-mediated IgG production in vitro and induce germinal center formation and anti-viral antibodies in response to virus infection. These mouse MP Tfh cells share a similar phenotype to human circulating Tfh cells that are increased in Sjögren's syndrome patients. Although Foxp3-positive circulating T follicular regulatory (Tfr) cells are normal, a proportion of circulating Tfh cells from patients express increased levels of T-bet, which is associated with high levels of inflammatory pathology. Thus, although they do not require overt infection for their development, MP Tfh cells are important for protective immune responses, and dysregulated MP Tfh responses may play a role in autoimmunity.