56. Attenuate alloimmune response to induce transplant tolerance by deletion CD98hc in mouse T lymphocyte

Introduction: CD98 heavy chain (CD98hc), encoded by Slc3a2, is a widely expressed vertebrate membrane protein whose functions are known as facilitating amino acid transporter and mediating integrin signaling. Although CD98hc expressed much higher in proliferating lymphocyte, little is known about its function on T lymphocyte mediated immune response to alloantigens.
Methods and results: First, we successfully deleted CD98hc in T cells by crossing mice bearing a loxP-flanked Slc3a2 allele with those expressing Cre recombinase in T cells (CD4-Cre+). T cell-specific deficient of CD98hc resulted in lower responses to alloantigens in mixed lymphocyte reaction assay. Heterotopic cardiac transplantation was then performed from BALA/ c (H-2Kd) to CD98hclox/-CD4-Cre+/C57BL/6 (H-2Kb) or control littermate C57BL/6 (B6) mice. We found that all CD98hclox/-CD4-Cre+ recipients had indefinite graft survival (MST >100 days, n=8). In contrast, all B6 recipients suffered acute rejection (MST: 7.4±0.5 days, n=12). In consistent with cardiac graft survival, we found that graft infiltration cells of CD98hclox/-CD4-Cre+ recipients on POD7 were fewer than that of B6 recipients by FACS and immune-staining analysis. Also chemotaxis assay data revealed that migrated CD98hclox/-CD4- Cre+ lymphocyte were less than that of B6 in the presence of different concentration of chemokines CCL2, CCL5. In addition, a neutralizing antibody (clone 26-24) specific against CD98hc prolonged graft survival (MST: 13.4±2.7 days, n=8, P=0.0186) in B6 recipients after they received BALB/c mice heart.
Conclusions: Hence our date indicated that T cell-specific deficient of CD98hc impaired proliferate in response to alloantigens and decreased migration ability result in inducing immune tolerance after cardiac transplantation. Moreover, application of the blocked of CD98hc by monoclonal antibody is effective in the treatment of acute cardiac allograft rejection.