Modern vaccine and other immune strategies take for granted that the mechanisms that define the B cell antibody repertoire and underlie B cell primary and memory responses are relatively well understood. However, our recent studies underscore an important gap in this understanding. We have plays a key role in regulating B- 1a autoantibody production. To explore the mechanisms underlying this CTLA4-mediated B-1a regulation, we generated conditional knockout mice (CKO) in which CTLA4 is specifically deleted in B cells but remains normal in T cells. Our preliminary studies show that ablation of CTLA4 in B cells results in a) increased B-1a expansion; b) spontaneous formation of germinal centers (GC) in spleen; and c) a striking increase in hyper-mutated class- switched B cells whose origins (B-1a or other B) remain elusive. As a result, serum IgG and IgE are remarkably elevated in CTLA4 B cell CKO mice. Intriguingly, we also find that T follicular helper cells (CXCR5+PD-1hiBcl6+), a specialized CD4 T effector subset that provides essential help for GC B cells, is spontaneously induced in CTLA4 B cell CKO mice. Consistent with this finding, we further find that like typical GC responses induced by immunizing with foreign antigens, the spontaneous GC responses in CTLA4 B cell CKO depend on CD4 T cells and CD40 signaling. Finally, we find that autoreactive IgG and IgE, e.g., anti-ANA and anti-dsDNA, are generated in CTLA4 B cell CKO mice and that these mutant mice develop autoimmune pathology as animals age. Taken all together, these findings strongly argue that, as in T cells, CTLA4 also acts as a key checkpoint regulator for B-1a function. In studies here, we focus on the cellular and molecular mechanism(s) that mediate CTLA4 regulation of B- 1a activation, thereby controlling B-1a IgM and IgG natural antibody production and their other immune functions. Our findings potentially offer insights into the mechanisms operating in antibody-mediated autoimmune diseases. Beyond autoantibody production, our studies can be expected to elucidate previously unrecognized roles that B- 1a cells play in maintaining immune homeostasis and self-tolerance. Of practical interest, studies here may offer insights into the mechanism underlying the pathologic autoimmune responses associated with the otherwise promising ?CTLA4 blockade? immune therapy for advanced human neoplasms.
CTLA4, a protein found in both man and mouse, is a well-known regulator of T-cell mediated autoimmunity. Our laboratory recently recognized that in mice, CTLA4 is expressed in B-1a cells, a unique B cell subset known to produce autoantodies and to be active in autoimmune conditions. Studies here focus on the mechanisms through which CTLA4 expression in this subset promotes autoimmunity and plays key regulatory roles in autoantibody production.