Aging is associated with important clinical problems such as increased susceptibility to infections and certain malignancies. Mechanisms underlying immunosenescence are not completely understood but evidence has been collected that T cell function declines in the elderly. The investigators have made the observation that, in a subset of aged individuals, CD4+ T cells have lost the expression of the important co-stimulatory molecule, CD28. Susceptibility to losing CD28 expression appears to be genetically determined and occurs in about 30% of the Caucasian population. The investigators have also shown that CD4+ CD28 null T cells are deficient in the expression of CD40 ligand (CD40L) and therefore lack a second critical molecule that is important in facilitating T-B cell interactions and the development of humoral immune responses. Preliminary data indicate that the downregulation of CD28 on CD4+ T cells is caused by a transcriptional block. The investigators have evidence that two possibly novel nuclear DNA binding activities correlate with CD28 expression and that the presence of these binding activities is age dependent. The investigators propose that the loss of CD28 is a critical event in immunosenescence and that understanding mechanisms of CD28 gene expression will provide novel agents for interventions intended to correct immune hyporesponsiveness in the elderly. The investigators are planning to examine the basal transcriptional machinery regulating CD28 gene expression and to identify the cis-acting elements required for CD28 expression. The investigators will continue their studies aimed at defining the binding motifs within a 67 bp segment and to molecularly characterize the corresponding DNA binding proteins that have been shown to correlate with CD28 expression. The investigators propose to clone and sequence the corresponding genes and to confirm differential expression in CD28+ and CD28null T cells. The influence of senescence on the expression of these proteins will be analyzed in vitro after replicative senescence as well as in vivo by comparing young and old individuals. Finally, the investigators will pursue the question whether CD40L expression can be restored by reconstituting CD28 expression in deficient T cells. This question will be examined by comparing helper cell functions of CD4+ CD28null and CD4+ CD28null T cell clones derived from the same progenitor cell and by transfecting CD28-deficient CD4+ T cell clones with the CD28 gene. Studying molecular and functional aspects of CD4+ CD28null T cells provides a unique opportunity to address age- related dysfunction in T cells. Preventing the accumulation of CD4+ CD28null T cells might be a primary target for immune therapy in aging individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG015043-01A1
Application #
2704312
Study Section
Special Emphasis Panel (ZRG4-GRM (01))
Project Start
1998-08-15
Project End
2003-06-30
Budget Start
1998-08-15
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
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