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- PD-1 and ICOS are coexpressed in T follicular helper cells but define three stages of maturation of T follicular regulatory cellsPublication . Ribeiro, Filipa; Antunes, Diogo; Pires, Ana R.; Rino, José; Filipe, Beatriz; Jesus, Kátia; Correia, Ricardo; Fonseca, Válter R; Kumar, Saumya; Graca, LuisHumoral responses to infection or vaccination require T cell-B cell interactions. T follicular helper (TFH) cells drive germinal center (GC) responses by providing help to B cells, whereas T follicular regulatory (TFR) cells regulate them. Both mature GC-located TFH and TFR cells are widely characterized by the expression of ICOS and PD-1. However, although human TFR cells share many phenotypic characteristics with TFH cells, we found that ICOS and PD-1 are up-regulated differently in each. Although TFH cells express these proteins synchronously during maturation, they define three maturation stages in TFR cells. TFR cells in an intermediate maturation stage express ICOS, and it is only at the last stage of differentiation that both molecules are expressed at high levels. Although most TFR cells within the B cell follicle are PD-1-, the TFR within the GC are ICOS+PD-1+. These results show that TFH and TFR cells within human lymphoid tissue follow distinct maturation stages.
- Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulationPublication . Ribeiro, Filipa; Romão, Vasco C.; Rosa, Sara; Jesus, Kátia; Agua-Doce, Ana; Barreira, Sofia; Martins, Patrícia; Silva, Susana; Nobre, Ema; Bugalho, Maria João; Fonseca, Valter R; Fonseca, João Eurico; Graca, LuisAutoantibodies are produced within germinal centers (GC), in a process regulated by interactions between B, T follicular helper (Tfh), and T follicular regulatory (Tfr) cells. The GC dysregulation in human autoimmunity has been inferred from circulating cells, albeit with conflicting results due to diverse experimental approaches. We applied a consistent approach to compare circulating Tfr and Tfh subsets in patients with different autoimmune diseases. We recruited 97 participants, including 72 patients with Hashimoto's thyroiditis (HT, n = 18), rheumatoid arthritis (RA, n = 16), or systemic lupus erythematosus (SLE, n = 32), and 31 matched healthy donors (HD). We found that the frequency of circulating T follicular subsets differed across diseases. Patients with HT had an increased frequency of blood Tfh cells (p = 0.0215) and a reduced Tfr/Tfh ratio (p = 0.0338) when compared with HD. This was not observed in patients with systemic autoimmune rheumatic diseases (RA, SLE), who had a reduction in both Tfh (p = 0.0494 and p = 0.0392, respectively) and Tfr (p = 0.0003 and p = 0.0001, respectively) cells, resulting in an unchanged Tfr/Tfh ratio. Activated PD-1+ICOS+Tfh and CD4+PD-1+CXCR5-Tph cells were raised only in patients with SLE (p = 0.0022 and p = 0.0054), without association with disease activity. Our data suggest that GC dysregulation, assessed by T follicular subsets, is not uniform in human autoimmunity. Specific patterns of dysregulation may become potential biomarkers for disease and patient stratification.