Harnessing the regulatory properties of B cells in the therapy of autoimmune disease. B cells are conventionally regarded as effector cells capable of producing antibodies against invading pathogens or, in the case of autoimmunity, against self-antigens. However, a body of evidence is now emerging, suggesting that B cells also play a regulatory role in the evolution of immune responses, chiefly through their interactions with T cells. I was amongst the first three groups in the world to identify a novel subset of B cells with strong suppressive capacity. Our original observation showed that activation of arthritogenic splenocytes with agonistic anti-CD40 gave a raise to a B cell population producing high levels of interleukin-10 (IL-10) and low levels of Interferon-? (IFN-?). Adoptive transfer of this B cell subset prevents disease development and ameliorates established arthritis (JEM, 2003). In 2007 we have phenotypically identified regulatory B cells and demonstrated that they are contained within the transitional 2 B cells subset (T2-Breg). (JI 2007)(Trends in Immunol. 2008). We are currently translating the results from the experimental model to healthy individuals as well as to patients with rheumatoid arthritis and to patients with SLE and have recently "pinned down" the phenotype and the mechanisms of action. Anti-TNF? therapy regulates CD4+CD25high T cells levels and function in rheumatoid arthritis. Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). We have demonstrated that regulatory T cells isolated from patients with active RA, although still anergic, were unable to suppress pro-inflammatory cytokines released by T cells and monocytes. In addition, these regulatory T cells lack the ability to convey a suppressive phenotype to neighbouring effector T cells. The functional defect was not permanent, as suppressive activity was restored after anti-TNF? treatment. Furthermore, anti-TNF? treatment lead to a significant rise in the peripheral blood regulatory T cells of RA patients responding to this treatment, which correlated with a reduction in C Reactive Protein (CRP). This work was done in collaboration with Prof. M. Ehrenstein and was the first study demonstrating that regulatory T cells are functionally compromised in RA, suggesting that modulation of regulatory T cells by anti-TNF_ therapy may be a further mechanism by which this disease is ameliorated (2004,JEM). Consequentially, we have extended our previous observation and demonstrated that anti-TNF? blockade can lead to induction of regulatory T cells and has the potential for restoring tolerance (2007 JEM). Recently we have characterized the molecular defect of regulatory T cell in patients with RA and unravelled that the lack of suppression is due to an abnormal recirculation of CTLA-4, molecule important for the maintenance of tolerance.