The role of CD4 T cell immunity to cytomegalovirus in immunosenescence

DFG project PA 361/11-1

Longitudinal studies performed under the aegis of the EU project “T-Cells in Ageing”, T-CIA, and its predecessors (ImAginE, EUCAMBIS), have confirmed that survival in very elderly people is associated with certain immunological parameters, most strikingly, a helper:cytotoxic cell (CD4:CD8) ratio of < 1 (high risk group). This is caused by the accumulation of dysfunctional apoptosis-resistant CD8 cells, and slight decreases in the number of CD4 cells. Compared to the middle-aged, the CD8 population in the very elderly (>85 yr) contains increased numbers of different clones which are mostly specific for CMV. However, in the terminal phase, loss of clonal heterogeneity is closely associated with mortality. The reasons for these clonal expansions and contractions, and for the accumulation of dysfunctional CD8 cells, are not known. The influence of CD4 helper cells and CD4 T-regulatory cells (Treg) on maintaining appropriate CD8 immunity has not yet been tested. We therefore plan to quantify functional CMV-specific CD4 cells in the elderly using class II HLA-DR-CMV multimers to detect CMV-specific T cell receptor-bearing cells, antibody panels to identify T cell subsets, and functional tests to establish the fraction of CMV-TCR-bearing cells capable of responding to specific antigen (by measuring proliferation, signal transduction, cytokine production, cytotoxicity). The same tests will be performed on CD8 cells from the same donors, using HLA-A and -B-CMV multimers. The function of both CD4 and CD8 CMV-specific cells will be challenged using autologous T-reg. We will seek differences between young donors and old donors with a CD4:8 ratio > 1 or < 1. Thus, we will be testing the following hypotheses: 1) that altered frequencies of CMV-specific CD4 as well as CD8 cells are found in ageing and especially in individuals with a CD4:8 ratio < 1; 2) that the properties of these CD4 cells, like their CMV-specific CD8 counterparts, will also be aberrant, but may show enhanced rather than decreased susceptibility to apoptosis; 3) that the number and function of Tregs differentially modulate response to CMV in old individuals; and 4) that these changes will be deleterious for healthful longevity and form part of the “immune risk profile” which we have previously proposed.