Aging of the immune system has significant impact on the efficacy of vaccination. Immune competence startsto be compromised after the age of 50 in healthy individuats and earlier in patients with autoimmune diseasesor a history of chemotherapy. Most vaccination strategies are developed in young adults and need to beoptimized to meet the needs of the middle-aged or elderly immune system. We hypothesize that thedominant mechanisms generating the clinical picture of immune senescence are (1) a reduced ability ofdendritic cells to induce T-cell responses, (2) a contraction of the diversity of the T-cell receptor repertoire,and (3) cellular senescence of naive and memory T cells. With the decline of thymic function, the repertoireof naive T cells contracts, restricting the availability of T-cell receptors that have an optimal fit for pathogenicantigens. Naive and memory T cells are under replicative stress, both from antigen-specific and fromhomeostatic proliferation. As a consequence, telomeres are eroded with age, limiting the ability of T cells torespond with clonal expansion. Senescence of memory T cells has been associated with changes in geneexpression that are detrimental to memory cell function, such as loss of CD28 and the gain of killer cellimmunoglobulin-like receptors (KIRs).
Specific aims have been designed to identify the immunologicalpathways that are compromised and to develop strategies to overcome these deficits.
Specific Aim 1 willfocus on primary T-cell responses, memory T-cell responses are examined in Specific Aim 2. We willcorrelate primary T-cell responses in an in vitro system with the age of the donor, and we will use functionalassays as well as genomic and proteomic studies to identify pathways that correlate with decreasedresponsiveness or proliferative arrest of naive T cells. These pathways will be targeted to improve primaryimmune responses. We will test the relevance of these observations in vivo and determine whether therepertoire of T cells induced by anthrax vaccination is age-dependent.
In Specific Aim 2, we will usefunctional assays and genomic and proteomic studies to identify defects in memory cell responses. CD28loss, KIR expression and other newly identified pathways will be targeted to overcome these defects.Additional studies in vivo will determine how age-dependent mechanisms influence T memory cellhomeostatic proliferation, long-term persistence of vaccinia-specific memory cells and the ability of memorycells to respond to antigenic rechallenge in vivo. Taken together, these studies will develop strategies toimprove primary and recall responses in middle-aged and elderly individuals to vaccination.
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