The impact of T cells upon anti-chromatin B cells in healthy and autoimmune mice

The phenotype and fate of anti-chromatin B cells has been tracked in healthy and autoimmune-prone MRL-lpr/lpr (Fas-deficient) mice. To isolate the role of the lpr and gld mutations on B cell fate, away from the MRL background, which is itself autoimmune-prone, we bred BALB-lpr/lpr and BALB-gld/gld (mutated in FasL) mice. Anti-chromatin B cells are prevented from making autoantibodies in healthy mice but produce antibodies in lpr/lpr and gld/gld mice by ten to twelve weeks of age. In the case of Fas/Fast-deficient mice, an increase in CD4+ T cell activation is apparent early, even prior to autoantibody production. Changes in the dendritic cell compartment are also strikingly apparent at young ages. Anti-chromatin B cells respond in some measures to this environment but do not initially undergo terminal differentiation. To learn more about how anti-chromatin B cells respond to T cell help in vivo, we have used a model system to provide cognate T cell help. Using this system, we show that anti-chromatin B cells from nonautoimmune mice respond readily to T cell help in vivo. Both Th1 and Th2 cells have the ability to help anti-chromatin B cells, although the former cell type requires a certain threshold of IFN-γ expression to be fully effective. Strikingly, CD4+CD25+ T regulatory (Treg) cells are capable of suppressing anti-chromatin B cell help provided by non-differentiated T helper (Th), Th1, and Th2 cells. Treg cells allow some of the primary events associated with a productive T-B cell interaction to occur in vivo but do diminish B and T cell survival and autoantibody production. Treg cells must be co-injected with the Th cells for full suppressive effect. Thus, we propose that B cell tolerance to nuclear antigens relies heavily on maintaining tolerance in the T cell compartment. One mechanism for doing so appears to be via the suppressive effects of Treg cells