T CELLS AND AGING

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the Applicant's Abstract): 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.
StatusNot started

Funding

  • National Institute on Aging: $224,343.00
  • National Institute on Aging: $290,143.00
  • National Institute on Aging: $298,809.00
  • National Institute on Aging: $306,000.00
  • National Institute on Aging: $306,000.00
  • National Institute on Aging: $208,259.00

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