Abstract
Abstract Increased levels of CD40L have been observed on CD4 T cells of patients with systemic lupus erythematosus (SLE) and in several murine models of lupus-like disease. Notably, elevated/prolonged expression of CD40L corresponds to the expansion and survival of autoreactive B cells. However, targeting CD40L as a potential therapeutic has been challenging due to the development of off-target events. We have developed a unique mouse model termed CD40LΔ5 (Δ5) which lacks a stability element in the 3’ UTR of the CD40L message and upon immunization, shows decreased CD40L expression on Tfh cells leading to both reduced GC B cell survival and a critically disproportional loss of pre-memory B cells. Using our Δ5 model, we sought to determine whether reduced CD40L could substantially alter the development of disease in an adoptive transfer model of lupus based upon MHC II incompatibility. B6 WT mice were engrafted with CD4 T cells from bm12-WT or bm12-Δ5 mice and analyzed for splenic lymphocyte subsets. In mice that received Δ5 T cells, total CD4 and CD8 subsets were unchanged compared to mice receiving WT cells, however, there was an increase and decrease of Tfh cells in male and female mice, respectively. This was confirmed by a corresponding change in Tfh proliferation as measured by staining for Ki67. Total CD19 B cells were increased in male mice receiving D5 T cells. Finally, intracellular staining of T cell cytokines was different in male and female mice receiving the Δ5 T cells as was the distribution of GC B cell subsets, including pre-memory B cells. Together our results suggest that limiting CD40L in T cells at an early stage of bm12-induced lupus has a significant effect on the maturation of GC subsets that is closely aligned with the sex of the WT recipient mice. Supported by AAI Careers in Immunology Fellowship 2019-2020
Published Version
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