Slc26a3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse.

Members of the solute carrier 26 (SLC26) family have emerged as important players in mediating anions fluxes across the plasma membrane of epithelial cells, in cooperation with the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Among them, SLC26A3 acts as a chloride/bicarbonate exchanger, highly expressed in the gastrointestinal, pancreatic and renal tissues. In humans, mutations in the SLC26A3 gene were shown to induce congenital chloride-losing diarrhea (CLD), a rare autosomal recessive disorder characterized by life-long secretory diarrhea. In view of some reports indicating subfertility in some male CLD patients together with SLC26-A3 and -A6 expression in the male genital tract and sperm cells, we analyzed the male reproductive parameters and functions of SLC26A3 deficient mice, which were previously reported to display CLD gastro-intestinal features. We show that in contrast to Slc26a6, deletion of Slc26a3 is associated with severe lesions and abnormal cytoarchitecture of the epididymis, together with sperm quantitative, morphological and functional defects, which altogether compromised male fertility. Overall, our work provides new insight into the pathophysiological mechanisms that may alter the reproductive functions and lead to male subfertility in CLD patients, with a phenotype reminiscent of that induced by CFTR deficiency in the male genital tract.

ADAP deficiency combined with costimulation blockade synergistically protects intestinal allografts.

Adhesion and degranulation promoting adapter protein (ADAP) plays an important role in T cell activation. ADAP deficiency was recently found to prolong heart graft survival in mice. We investigated the role of ADAP in intestinal transplantation and the synergistic effect of ADAP deficiency and Costimulation blockade (CB). T cell proliferation and cytotoxic T lymphocyte (CTL) activity were determined. MHC mismatched intestinal allografts was transplanted heterotopically. Anti-CD40L antibody was applied to the recipient. Upon stimulation with allogenic dendritic cells (DC), ADAP-deficient (ADAP-/-) T cells displayed impaired proliferative responses compared with that of wild-type (WT) T cells. In contrast, the CTL activity in ADAP-/- mice was comparable with that of WT mice. Rejection of intestinal allografts was ameliorated, but not prevented in ADAP-/- mice. Although CB alone was not sufficient to mitigate the rejection, the combination of CB and ADAP deficiency profoundly inhibited rejection. This was accompanied by less infiltration and activation of host lymphocytes in the gut-associated lymphoid tissue of intestinal allografts. ADAP deficiency combined with CB protected the intestinal allografts synergistically. ADAP could be a novel target in the induction phase of the immune responses in organ transplantation.