Glycosylation changes in hFUT1 transgenic mice increase TCR signaling and apoptosis resulting in thymocyte maturation arrest.
Glycosylation of cell surface proteins is important in thymocyte maturation. In particular, the level of sialylation of key glycoproteins such as CD45 is believed to play a major role in regulating TCR signaling, adhesion and apoptosis of developing thymocytes. We show here that transgenic expression of human alpha1-2 fucosyltransferase (hFUT1) in mice resulted in a marked shift from sialylation to fucosylation of thymocyte glycoproteins. This was associated with a significant reduction in thymocyte number, an increased rate of apoptosis in double positive and single positive thymocytes, and a maturation arrest at TCR-dependent developmental transitions reminiscent of CD45 deficiency. Indeed, CD45RB dimerization was elevated in hFUT1 thymocytes, consistent with its hyposialylation, and there was a corresponding increase in phosphorylation of the TCR-associated protein Lck. However, contrary to the reduced TCR signaling in CD45 null mice, basal and stimulated TCR signaling was higher in hFUT1 thymocytes than in wild type thymocytes. Our results therefore demonstrate that aberrant expression of a single glycosyltransferase can profoundly affect thymopoiesis, although the relative involvement of CD45-dependent and -independent mechanisms is yet to be determined.
D000818:Animals; D017304:Annexin A5; D017209:Apoptosis; D002454:Cell Differentiation; D019281:Dimerization; D005647:Fucosyltransferases / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D017493:Leukocyte Common Antigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019158:N-Acetylneuraminic Acid; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism; D000097631:Galactoside 2-alpha-L-fucosyltransferase
D017304:Annexin A5; D005647:Fucosyltransferases; D017493:Leukocyte Common Antigens; D019158:N-Acetylneuraminic Acid; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C497262:Zap70 protein, mouse