Aberrant humoral immune responses and intestinal homeostasis in Cd38 Bst1 double knockout mice

Ayano Yahagi, Masanori Iseki, Keisuke Yaku, Takashi Nakagawa, Motoyuki Itoh, Tomoyuki Mukai, Katsuhiko Ishihara

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.

Immunohorizons

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10.1093/immhor/vlaf029

https://doi.org/10.1093/immhor/vlaf029