No abstract

Selective IgA deficiency (IgAD) is the most common primary antibody deficiency in the western world with affected individuals suffering from an increased burden of autoimmunity, atopic diseases and infections. It has been shown that IgAD B cells can be induced with germinal center mimicking reactions to produce IgA. However, IgA is the most prevalent antibody in mucosal sites, where antigen-independent responses are important. Much interest has recently focused on the role of TLR9 in both naïve and mature B cell differentiation into IgA secreting plasma cells. Here, we analyze the phenotype and function of T and B cells in individuals with IgAD following IgA-inducing CpG-TLR9 stimulations. The IgAD individuals had significantly lower numbers of transitional B cells (CD19+CD24hiCD38hi) and class-switched memory B cells (CD20+CD27+IgD−) ex vivo. However, proportions of T cell populations ex vivo as well as in vitro induced T effector cells and T regulatory cells were comparable to healthy controls. After CpG stimulation, the transitional B cell defect was further enhanced, especially within its B regulatory subset expressing IL-10. Finally, CpG stimulation failed to induce IgA production in IgAD individuals. Collectively, our results demonstrate a defect of the TLR9 responses in IgAD that leads to B cell dysregulation and decreased IgA production.

CD8+ Tregs display an immunoregulatory activity and may play an essential role in the immunopathology of several diseases. Therefore, their therapeutic potential is exquisite and further studies on their differentiation and function are essential. The aim of this study was to evaluate the role of the innate immune system in CD8 + iTreg differentiation and function. Naive human CD8 + CD25 À CD45RA + T cells were cultured in Treg-inducing conditions with or without IL-1b, TNFa or monocyte-derived dendritic cells (DCs). The differentiation of CD8 + CD127 À CD25 hi FoxP3 hi -induced Tregs (CD8 + iTregs) is dependent on TGF-b1 and IL-2, which had synergistic effect upon their differentiation. CD8 + iTregs were also induced in a coculture with allogeneic mature DCs (mDCs). The CD8 + iTregs suppressive function was confirmed, which was diminished in the presence of IL-1b and TNFa. The IL-1b-prevented suppressive function was associated with reduced secretion of IL-10 and IFNc, whereas the presence of TNFa did not affect their secretion. Furthermore, the presence of TNFa reduced IL-10 and TGF-b1 secretion by CD8 + iTregs, whereas only IL-10 secretion was decreased by IL-1b. Together, these results suggest that IL-1b and TNFa prevent IL-2-and TGF-b1-driven CD8 + iTregs suppressive function in human T cells. Such pro-inflammatory innate immune response possibly mediates its negative tolerogenic effect through reduced IFNc-, IL-10-and TGF-b1-driven mechanism.