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-Dystroglycan is involved in positive selection of thymocytes by participating in immunological synapse formation

Yanping Gong^*,1, Ruihua Zhang^*,1, Jinping Zhang^*, Lin Xu^*, Feng Zhang^*, Wei Xu^*, Ying Wang^*, Yiwei Chu^* and Sidong Xiong^,2

^* Institute for Immunobiology, Department of Immunology, Shanghai Medical College of Fudan University, Shanghai, China; and

Immunology Division, E-Institutes of Shanghai Universities, Shanghai, China

²Correspondence: Department of Immunology, Shanghai Medical College of Fudan University, 138 Yixueyuan Rd., Shanghai 200032, China. E-mail: sdxiongfd{at}126.com

-Dystroglycan has been proved to be involved in lymphocyte activation by participating in immunological synapse (IS) formation. Considering the existence of IS formation in thymic development, we questioned whether -dystroglycan was expressed in thymus and influenced thymic development. In this study, we demonstrated that -dystroglycan was expressed on fetal thymocytes, especially on double-positive (DP, CD4⁺CD8⁺) cells. Blocking -dystroglycan by treatment of fetal thymus organ culture (FTOC) with anti--dystroglycan antibody IIH6C4 decreased the number of DP cells compared with nontreated or isotype antibody controls. Down-regulation of -dystroglycan by retroviruses carrying antisense cDNA of dystroglycan in reaggregate thymus organ culture (RTOC) further confirmed these results. Enhanced apoptosis of DP cells was observed after blocking -dystroglycan. Interestingly, we found that blocking -dystroglycan reduced IS formation between DP cells and thymic epithelial cells. Furthermore, blocking -dystroglycan up-regulated CD95/CD95L expression and reduced Bcl-2 expression on DP cells in the developing thymus. Finally, the increase in the apoptosis of DP cells was associated with a consequent decrease in the positive selection, as indicated by the reduction of both ERK phosphorylation in DP cells and single-positive (SP, CD4⁺ or CD8⁺) cell outcome. Altogether, these results indicated that -dystroglycan was involved in positive selection of thymocytes by participating in the IS formation.—Gong, Y., Zhang, R., Zhang, J., Xu, L., Zhang, F., Xu, W., Wang, Y., Chu, Y., Xiong, S. -Dystroglycan is involved in positive selection of thymocytes by participating in immunological synapse formation.

Key Words: thymic development • fetal thymus organ culture • reaggregate thymus organ culture