Lrba participates in the differentiation of IgA+ B lymphocytes through TGFßR signaling.

Introduction: Lrba is a cytoplasmic protein involved in vesicular trafficking. Lrba-deficient (Lrba-/-) mice exhibit substantially higher levels of IgA in both serum and feces than wild-type (WT) mice. Transforming growth factor ß1 (TGFß1) and its receptors (TGFßR I and II) is essential for differentiating IgA+ B cells. Furthermore, increased IgA production suggests a potential connection between Lrba and the TGFßR signaling pathway in IgA production. However, the specific function of Lrba in B cell biology remains unknown. Aim: Given the increased IgA levels in Lrba-/- mice, the goal in this work was to explore the lymph organs where the switch to IgA occurs, and if TGFßR function is affected. Methods: Non-immunized Lrba-/- mice were compared with Lrba+/+ mice. IgA levels in the serum and feces, as well as during peripheral B cell development, were determined. IgA+ B cells and plasma cells were assessed in the small intestine and secondary lymphoid organs, such as the spleen, mesenteric lymph nodes, and Peyer's patches. The TGFßR signaling pathway was evaluated by determining the expression of TGFßR on B cells. Additionally, SMAD2 phosphorylation was measured under basal conditions and in response to recombinant TGFß. Finally, confocal microscopy was performed to investigate a possible interaction between Lrba and TGFßR in B cells. Results: Lrba-/- mice exhibited significantly higher levels of circulating IgA, IgA+ B, and plasma cells than in peripheral lymphoid organs those in WT mice. TGFßR expression on the membrane of B cells was similar in both Lrba-/- and Lrba+/+ mice. However, intracellular TGFßR expression was reduced in Lrba-/- mice. SMAD2 phosphorylation showed increased levels under basal conditions; stimulation with recombinant TGFß elicited a poorer response than in that in Lrba+/+ B cells. Finally, we found that Lrba colocalizes with TGFßR in B cells. Conclusion: Lrba is essential in controlling TGFßR signaling, subsequently regulating SMAD2 phosphorylation on B cells. This mechanism may explain the increased differentiation of IgA+ B cells and production of IgA-producing plasma cells.

Stability and plasticity of regulatory T cells in health and disease.

The mechanisms that negatively regulate inflammation upon a pathogenic stimulus are crucial for the maintenance of tissue integrity and organ function. T regulatory cells are one of the main drivers in controlling inflammation. The ability of T regulatory cells to adapt to different inflammatory cues and suppress inflammation is one of the relevant features of T regulatory cells. During this process, T regulatory cells express different transcription factors associated with their counterparts, Th helper cells, including Tbx21, GATA-3, Bcl6, and Rorc. The acquisition of this transcription factor helps the T regulatory cells to suppress and migrate to the different inflamed tissues. Additionally, the T regulatory cells have different mechanisms that preserve stability while acquiring a particular T regulatory cell subtype. This review focuses on describing T regulatory cell subtypes and the mechanisms that maintain their identity in health and diseases.