Human blood T_fr cells are indicators of ongoing humoral activity not fully licensed with suppressive function

Germinal center (GC) responses are controlled by T follicular helper (T_fh) and T follicular regulatory (T_fr) cells and are crucial for the generation of high-affinity antibodies. Although the biology of human circulating and tissue T_fh cells has been established, the relationship between blood and tissue T_fr cells defined as CXCR5⁺Foxp3⁺ T cells remains elusive. We found that blood T_fr cells are increased in Sjögren syndrome, an autoimmune disease with ongoing GC reactions, especially in patients with high autoantibody titers, as well as in healthy individuals upon influenza vaccination. Although blood T_fr cells correlated with humoral responses, they lack full B cell-suppressive capacity, despite being able to suppress T cell proliferation. Blood T_fr cells have a naïve-like phenotype, although they are absent from human thymus or cord blood. We found that these cells were generated in peripheral lymphoid tissues before T-B interaction, as they are maintained in B cell-deficient patients. Therefore, blood CXCR5⁺Foxp3⁺ T cells in human pathology indicate ongoing humoral activity but are not fully competent circulating T_fr cells.