T cells, but not TLRs, control Act1-driven autoimmunity (93.28)

Abstract

Abstract Act1 is a negative regulator of B lymphocyte-activating factor (BAFF) and CD40 signaling and is a key modulator of systemic autoimmunity, since Act1-deficient mice develop symptoms of severe autoimmune disease. As both T cell help and TLR signaling are known to contribute to autoimmune disease, mice deficient in either functional T cells (TCRb/d knockout) or TLR signaling (IRAK4 knockout) were crossed onto the Act1 autoimmune-prone background. Importantly, IRAK4-deficient animals are devoid in all TLR signaling, except TLR3. Splenomegaly, lymphademopathy, hypergammaglobulinemia, antigen-specific autoantibodies and immune complex deposition are all reduced in Act1 / TCRb/d triple deficient mice but not in Act1 / IRAK4 double deficient mice, indicating that T cells but not TLRs are required for Act1-driven autoimmunity. Additionally, as it is known that the numbers of transitional B cells are increased in the absence of functional Act1, preliminary cell population analysis demonstrates that in the absence of T cells, transitional B cells are still increased in number. Taken together, this indicates that early B cell development is not dependent upon the presence of T cells; whereas, the activation of autoreactive B cells is dependent upon T cells. Furthermore, both of these events appear to be independent of IRAK4 and potentially TLR signaling.