Enhanced T lymphocyte function in young and old mice through changes in surface glycoproteins.

It has been proposed that large, bulky, heavily glycosylated glycoproteins on the T cell surface, including CD43, negatively regulate T cell-antigen presenting cell (APC) interactions, thereby inhibiting T cell activation. In agreement with this hypothesis, recent work in our lab has shown that aging results in the hyper-expression of glycosyl epitopes on CD43 on CD4 + T cells from aged mice and that treatment of CD4+ T cells with O-sialoglycoprotein endopeptidase (OSGE), which cleaves O-glycosylated proteins at the peptide backbone, is able to restore the ability of T cells from aged mice to form immunological synapses and to express early activation markers. These data have led us to hypothesize that aging results in the dysregulation of T cell surface glycosylation, leading to the hyper-expression of negative regulatory glycosyl moieties on the surface of T cells from aged animals. Our new results show that OSGE enhances the ability of CD4+ T cells from young and old mice to produce multiple cytokines at the mRNA and protein levels. A similar OSGE-mediated enhancement was observed in CD8 + T cells at the protein level. We have determined that the in vitro effects of OSGE are long lasting, making it potentially useful as an in vivo pharmacological tool to boost the immune response in the elderly. Treatment with some but not all sialidases induces a similar enhancement. We have shown that CD43 does not appear to be the primary molecule responsible for the effects mediated by the enzymes, as both OSGE and the sialidases are able to enhance T cell function in CD43 knockout mice. Other work in this thesis has demonstrated that there are age-dependent differences in the expression of mRNA for 8 glycosyltransferases in the CD4 + T cell population, giving us some insight into the potential mediators of the observed age-dependent changes in T cell function. In addition, we have used other glycosyl-specific enzymes in conjunction with lectin binding assays to determine that the age-related hyper-expression of Siaalpha(2,3)Gal/GalNAc-specific linkages may be important in dampening T cell function in the elderly. Taken together, the data suggest a model in which deregulation of glycosylation pathways in T cells from old mice might lead to hyper-expression of CD43-independent glycosyl moieties that interfere with T cell-APC interaction, thus contributing to age-dependent defects in T cell signaling and function. These findings provide us with a greater insight into the role of glycosylation in dampening immune function in the elderly, thus suggesting approaches that might improve immune function in aged humans and animals.Ph.D.Biological SciencesCellular biologyHealth and Environmental SciencesImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125615/2/3208422.pd