Natural TFH arise in the thymus and periphery of young naive mice

Abstract

Abstract T follicular helper cells (TFH) localize to B cell follicles and secrete Interleukin 21 (IL21), a cytokine that is vital for driving the proliferation of antigen-stimulated B cells within germinal centers and their subsequent differentiation into memory B cells and antibody-secreting plasma cells. Much of the current understanding of TFH is limited to studies following immunization of adult mice. Therefore, the ontological processes by which TFH naturally develop and express IL21 are poorly understood. Here we take advantage of a novel IL21-venus fluorescent protein reporter mouse to show that a major fraction of the earliest activated CD4 T cells that develop spontaneously in the thymi and the peripheries of young naive mice express IL21 within 2 weeks of birth. This population is rivaled in frequency only by FoxP3 natural T regulatory cells (nTREG) cells. Results from RNAseq profiling, their partial developmental dependence on IL6 and IL21 signaling and durability after adoptive transfers are all consistent with the generation of a novel, natural TFH (nTFH) population. This nTFH population is functionally defined by IL21 and is able to persist in that differentiation state in naive mice. We further show that thymic development of nTFH requires AIRE, while FoxP3 nTREG act in the periphery to restrain nTFH. We conclude that the precocious and robust presentation of nTFH in naive mice is caused by inherent self-reactivity that is developmentally driven by encounter with promiscuous self-antigens through AIRE. TREG are therefore the primary means by which nTFH are prevented from exercising their pathogenic potential in the periphery.