CMV is a ubiquitous beta-herpes virus that in immune competent hosts establishes a persistent life-long infection with few overt clinical sequelae. This peaceful co-existence is maintained by robust immune responses, particularly T cell responses, which in CMV-exposed adult humans average about 10% of the total memory repertoire. In most elderly subjects, CMV infection continues to be controlled, but there is increasing evidence that this control may be at the cost of immune responsiveness to new or episodically encountered pathogens. Such immune decline in the elderly - clinical """"""""immune senescence"""""""" -- has been associated with the increasing dominance and oligoclonality of the """"""""effector memory"""""""" T cell subset (primarily among CD8+ T cells), features that have been associated with CMV exposure and are characteristic of the large CMV-specific T cell response. We have proposed that persistent exposure to CMV, likely augmented in the elderly by progressive hypofunction of the CMV-specific T cell population and a consequent increase in the number of CMV reactivation episodes, drives the progressive expansion of increasingly oligoclonal CMV-specific T cell populations, ultimately replacing and/or inhibiting the development of T cell populations reactive with other agents. In the proposed project, we plan to use the Rhesus Macaque (RM) aging model to address both the role of CMV infection in the development of immune senescence and the effect of aging on the structure and function of CMV-specific T cell memory by addressing the following specific aims:
Specific Aim 1 : Characterization of the frequency, phenotype, clonotypic complexity, turnover and function (cytokine synthesis, cytotoxicity, functional avidity, and global gene expression) of RhCMV-specific CD4+ and CD8+ memory T cells populations in adult vs. aged RM and determination of whether CMV-specific memory populations substantially contribute to aging-associated memory subset abnormalities, and whether characteristics of the CMV response correlate with diminished T cell responsiveness to unrelated Ags.
Specific Aim 2 : Characterization of the in vivo responsiveness and protective capabilities of CMV-specific memory T cells in adult vs. aged RM following overt RhCMV challenge, and determination of whether CMV re-infection contributes to senescence of the CMV-specific T cell populations or to global, aging-associated abnormalities in immune function.
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