CD38 Deficiency Ameliorates Chronic Graft- Versus-Host Disease Murine Lupus via a B-Cell-Dependent Mechanism

Abstract

The absence of the mouse cell surface receptor CD38 in Cd38^-/- mice suggests that this receptor acts as a positive regulator of inflammatory and autoimmune responses. Here, we report that, in the context of the chronic graft-versus-host disease (cGVHD) lupus inducible model, the transfer of B6.C-H2bm12/KhEg(bm12) spleen cells into co-isogenic Cd38^-/- B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells, and T-bet⁺CD11c^hi B cells, were observed in Cd38^-/- mice than in WT mice, while the expansion of Treg cells and Tfr cells was normal, suggesting that the ability of Cd38^-/- B cells to respond to allogeneic help from bm12 CD4⁺ T cells is greatly diminished. The frequencies of T-bet⁺CD11c^hi B cells, which are considered the precursors of the autoantibody-secreting cells, correlate with anti-ssDNA autoantibody serum levels, IL-27, and sCD40L. Proteomics profiling of the spleens from WT cGVHD mice reflects a STAT1-driven type I IFN signature, which is absent in Cd38^-/- cGVHD mice. Kidney, spleen, and liver inflammation was mild and resolved faster in Cd38^-/- cGVHD mice than in WT cGVHD mice. We conclude that CD38 in B cells functions as a modulator receptor that controls autoimmune responses.

Keywords: CD38; GC B cells; STAT1; T-bet+ B cells; anti-ssDNA antibodies; cGVHD lupus-like; inflammation; type I IFN-signature.