The link between circulating follicular helper T cells and autoimmunity

Individuals with autoimmunity often have an increased frequency of T cells bearing features of follicular helper T cells in their blood. Lucy Walker proposes that alterations in pathways that regulate autoimmunity are coupled to alterations in follicular helper T cell homeostasis. Follicular helper T (T-FH) cells provide help to B cells, supporting the formation of germinal centres that allow affinity maturation of antibody responses. Although usually located in secondary lymphoid organs, T cells bearing features of T-FH cells can also be identified in human blood, and their frequency and phenotype are often altered in people with autoimmune diseases. In this Perspective article, I discuss the increase in circulating T-FH cells seen in autoimmune settings and explore potential explanations for this phenomenon. I consider the multistep regulation of T-FH cell differentiation by the CTLA4 and IL-2 pathways as well as by regulatory T cells and highlight that these same pathways are crucial for regulating autoimmune diseases. The propensity of infection to serve as a cue for T-FH cell differentiation and a potential trigger for autoimmune disease development is also discussed. Overall, I postulate that alterations in pathways that regulate autoimmunity are coupled to alterations in T-FH cell homeostasis, suggesting that this population may serve as a core sentinel of dysregulated immunity.