Intrinsic versus environmental influences on T-cell responses in aging.

A decline in T-cell responses and a switch to memory T-cell predominance occur with aging. We have used the T-cell receptor (TCR) transgenic mouse model to study age-associated changes in T-cell responses that are a consequence of shifts in subset representation versus changes intrinsic to T cells versus changes in the 'aged' microenvironment. We found that naive transgene-expressing (Tg(+)) CD4(+) T cells from aged mice respond to antigen with reduced interleukin-2 (IL-2) production, decreased cell expansion, and limited differentiation to effectors. Comparable to the characteristic accumulation of memory phenotype T cells in aged humans and conventional rodents, Tg(+) CD4(+) T cells from old OTII and 6.5 TCR transgenic mice acquire a memory phenotype without immunization and become hyporesponsive. The naive Tg(+) CD8(+) T cells from aged 2C mice expressed activation markers, produced IL-2, proliferated, and differentiated into cytotoxic T lymphocytes as efficiently as their young counterparts. Responses by adoptive transferred Tg(+) cells from young mice, immunized in young and old conventional hosts, indicated that the host age influences the onset of cell division, level of cell expansion, and number of cytokine-producing cells. Co-transfer of dendritic cells (DCs) from young and less so from aged conventional mice partially restored responses. Furthermore, DCs and T-cell migration to draining lymphoid organs was reduced due to deficiencies intrinsic to aged cells and the aged environment. Thus, alterations in T-cell responses in aging are attributable to intrinsic and environmental influences.

Early antigen-specific response by naive CD8 T cells is not altered with aging.

Both a dramatic decline in CD8 responses and a switch to memory T cell predominance occur with aging. The extent to which the loss of responsiveness is the consequence of the accumulation of more differentiated vs intrinsically defective T cells (or both) has been unclear. Using similar conditions of Ag stimulation, we have examined the responses generated by CD8(+) cells isolated from aged TCR transgenic mice. We found that the naive transgene(+) CD8(+) cells from aged 2C mice expressed activation markers, produced IL-2, proliferated, and differentiated into cytotoxic T cells as efficiently as their young counterparts. The extent of responsiveness and the level of the responses were comparable in both age groups regardless of the stimulatory conditions used, i.e., partial costimulation/adhesion molecule expression on APCs, or presentation of lower affinity peptide or diminished peptide concentrations. By day 4 after Ag stimulation, no significant age-related differences were observed in the number of effector cells generated nor in the levels of secreted IL-2 or IFN-gamma. Upon restimulation of effector cells, IL-2 secretion and to a lesser extent TNF-alpha expression, but not IFN-gamma secretion, were diminished with age. These findings suggest that age-associated alterations in naive CD8 cell function are not found after primary stimulation, but may become apparent upon restimulation.