Aberrant humoral immune responses and intestinal homeostasis in <i>Cd38 Bst1</i> double knockout mice

Bone marrow stromal cell antigen-1 (BST-1)/CD157 and CD38 are ectoenzymes belonging to the mammalian ADP-ribosyl cyclase family. Previous analyses of BST-1-deficient mice (Bst1KO) in a 129×C57BL/6J(B6) mixed background revealed that BST-1 is a positive regulator of humoral immunity. Murine BST-1 has recently been known to be an enteroneuroimmune regulator. To further clarify the functions of the ADP-ribosyl cyclase family in vivo, in this study, we generated CD38 and BST-1 double knockout mice (Cd38Bst1DKO) and compared them with Cd38KO, Bst1KO, and wild-type (WT) mice in B6 backgrounds. Flow cytometry analyses of the spleen revealed a decrease in B cells in Cd38KO mice, an increase in marginal zone (MZ) B cells of Bst1KO, and a decrease in neutrophils in Cd38Bst1DKO mice. Compared with WT mice, Cd38Bst1DKO mice showed decreased basal serum immunoglobulins and antigen-specific antibodies in memory responses to a thymus-dependent antigen. Because BST-1 is selectively expressed on WT MZ B cells responsive to lipopolysaccharide, enhanced antibody production in Bst1KO and increased growth responses of Bst1KO B cells to lipopolysaccharide stimulation suggest a suppressive role for BST-1 in Toll-like receptor 4 signaling in MZ B cells. Additionally, aged Cd38Bst1DKO mice displayed enlarged mesenteric lymph nodes and elongated small intestine; these phenotypes appeared only in Cd38Bst1DKO and not in Cd38KO or Bst1KO mice, indicating a cooperative role of CD38 and BST-1 in intestinal homeostasis regulation. Overall, these findings indicate the involvement of ADP-ribosyl cyclases CD38 and BST-1 in regulating humoral immune responses and small intestine homeostasis.