Prior work has suggested a model for age-related T cell failure in which T cells from aged mice show both altered surface glycoprotein patterns and defects in cytoskeleton-dependent relocalization of surface glycoproteins. In addition, OSGE, a protease specific for O-linked glycoproteins including CD43, CD44, and CD45, has been shown to restore function of aged T cells to levels similar to that of T cells of young donors.
Three specific aims will address, respectively, (1) altered glycosylation, (2) cytoskeletal defects, and (3) repair of in vivo immune responses.
Aim 1 a will use a battery of specific lectins and glycosidases to determine which T cell surface glycoproteins contribute to diminished synapse formation, calcium signals, and cytokine expression in aged T cells.
Aim 1 b will use 2D electrophoresis and glycan-profiling to identify the T cell surface glycoproteins whose susceptibility to enzymatic digestion parallels the ability of the enzymes to improve T cell function.
Aim 1 c uses a multiplex RT-PCR approach to develop a listing of age-related changes in mRNAs for glycosides and glycosyl-transferases.
Aim 1 d evaluates specific surface glycoproteins, starting with CD44, CD45, CD4, and CDS, for susceptibility to the functionally relevant enzymes.
Aim 2 will explore the molecular basis for the failure of aged T cells to move molecules either into the synapse, or into the distal pole complex (DPC) opposite from the site of APC contact.
This aim explores two related hypotheses: (a) that T cell activation defects involve a failure to remove inhibitory molecules, including CD43 and protein phosphatases, from the synapse to the DPC, and (b) that the cytoskeletal defect involves altered phosphorylation of proteins in the ERM family.
Aim 3 will use two in vivo adoptive transfer systems to see if enzyme-treated T cells from aged donors show improved function in responses to hapten-carrier conjugates and to transplantable tumors. Improved knowledge of the basis for poor T cell function in old age, and the mechanisms by which enzyme exposure corrects these defects, could point to new ways to protect the elderly from cancer and infection, as well as to improvements in vaccination methods for old people.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Fuldner, Rebecca A
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Perkey, Eric; Fingar, Diane; Miller, Richard A et al. (2013) Increased mammalian target of rapamycin complex 2 signaling promotes age-related decline in CD4 T cell signaling and function. J Immunol 191:4648-55
Perkey, Eric; Miller, Richard A; Garcia, Gonzalo G (2012) Ex vivo enzymatic treatment of aged CD4 T cells restores cognate T cell helper function and enhances antibody production in mice. J Immunol 189:5582-9
Garcia, Gonzalo G; Miller, Richard A (2011) Age-related defects in the cytoskeleton signaling pathways of CD4 T cells. Ageing Res Rev 10:26-34
Garcia, Gonzalo G; Miller, Richard A (2011) Ex vivo enzymatic treatment of aged CD4 T cells restores antigen-driven CD69 expression and proliferation in mice. Immunobiology 216:66-71
Garcia, Gonzalo G; Miller, Richard A (2009) Age-related changes in lck-Vav signaling pathways in mouse CD4 T cells. Cell Immunol 259:100-4
Garcia, Gonzalo G; Sadighi Akha, Amir A; Miller, Richard A (2007) Age-related defects in moesin/ezrin cytoskeletal signals in mouse CD4 T cells. J Immunol 179:6403-9
Sadighi Akha, Amir A; Berger, Scott B; Miller, Richard A (2006) Enhancement of CD8 T-cell function through modifying surface glycoproteins in young and old mice. Immunology 119:187-94
Berger, Scott B; Sadighi Akha, Amir A; Miller, Richard A et al. (2006) CD43-independent augmentation of mouse T-cell function by glycoprotein cleaving enzymes. Immunology 119:178-86
Berger, Scott B; Sadighi Akha, Amir A; Miller, Richard A (2005) A glycoprotein endopeptidase enhances calcium influx and cytokine production by CD4+ T cells of old and young mice. Int Immunol 17:983-91
Sadighi Akha, Amir A; Miller, Richard A (2005) Signal transduction in the aging immune system. Curr Opin Immunol 17:486-91

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