Novel memory phenotype Tfh cells arise without overt antigen stimulation and are important for adaptive immune responses against viral infection

Abstract

Pathogen-induced memory Tfh cells exert a Tfh effector response during reinfection, regulating the generation of high-affinity antibodies. Here, we define novel memory-phenotype Tfh cells which are generated from naïve T cells under homeostatic conditions. These MP Tfh cells are phenotypically and functionally similar to pathogen-induced Tfh cells. MP Tfh cells can be defined by Tfh cell specific markers, CXCR5, BCL6, and PD-1, and markers of pathogen-induced long lived Tfh cells, FR4. T-bethigh MP T cells exert an innate-like Th1 response against viral infections. The transcription factor EGR2 is a repressor of T-bet function, and we found that MP Tfh cells are distinct from T-bethigh MP T cells but express EGR2 highly. Previously, we found Egr2 is required for MP T cell homeostasis and inflammation. Here, we observed that, in Egr2/3-/- CD4+ MP T cells, MP Tfh cell development is impaired. FR4+ EGR2 + MP T cells upregulate genes related to homeostatic proliferation, Tfh cell development and metabolic pathways of pathogen-induced memory Tfh cells. MP Tfh cells can exert an adaptive function by regulating B cell-mediated IgG production in vitro whereas MP Tfr cells are involved in suppressing MP Tfh cell function, thereby preventing excessive inflammation. In vivo, MP Tfh cells support germinal centre formation and induce neutralising antibody production after infection with vaccinia virus. Thus, MP Tfh cells with similar characteristics to pathogen-induced memory Tfh cells are developed in absence of environmental antigens and to date are the only CD4+ MP T cell subset associated with an adaptive immune response against viral infection.