T follicular regulatory cells infiltrate the human airways during the onset of acute respiratory distress syndrome and regulate the development of B regulatory cells

T follicular regulatory (Tfr) cell is a CXCR5⁺Foxp3⁺ subset of T regulatory (Treg) cell with critical roles in regulating germinal center responses and modulating the immune environment in the lymph nodes. Studies have shown that the proportion of Tfr cells may increase during acute inflammation. In this study, we investigated the role of Tfr cells in acute respiratory distress syndrome (ARDS). We found that Tfr cells were significantly enriched in peripheral blood and in mini-bronchoalveolar lavage (BAL) during the onset of ARDS. Notably, Tfr cells represented the majority of Treg cells in the mini-BAL samples. Tfr cells also showed CTLA-4, IL-10, and TGF-β expression, but compared to the non-Tfr Treg cells, the CTLA-4 and IL-10 expression by Tfr cells were slightly reduced. Both Tfr cells and non-Tfr Treg cells suppressed the proliferation of autologous CD4⁺CD25⁻ T cells; however, the Tfr cells displayed slightly reduced suppression capacity. Subsequently, B cells were co-incubated with autologous Tfr cells or non-Tfr Treg cells. Interestingly, we found that the frequency of IL-10⁺ Breg cells was significantly higher following incubation with Tfr cells than with non-Tfr Treg cells, which suggested that Tfr cells were more potent at inducing IL-10⁺ Breg cells. Together, these results demonstrated that Tfr cells were a similar but distinctive subset of Treg cells. Given that Tfr cells were strongly enriched in ARDS patients, especially in the lung infiltrates, they may exert critical ameliorating effects in ARDS.