(Verbatim from application) Our goal is to further our understanding of the decline in antigen-specific CD4 T cell responses in the aged.
In Aim 1, we will determine if all naive CD4 cells are defective in IL-2 production or if the defect is relegated to T cell subsets such as the Rhodamine 123dim cells. We will use T cell receptor (TcR) transgenic Tg) mice crossed with a mutant mouse strain in which the IL-2 gene is replaced with cDNA encoding green fluorescent protein to make age-related comparisons in the frequency of IL-2 producing cells and the relative amount of IL-2 produced per cell. The impact by the aged environment on naive T cell function will be determined using adoptive transfer. We will determine if the IL-2 deficiency can be overcome through co-immunization with inflammatory cytokines or stimulation with higher affinity peptides.
In Aim 2, we will define age-related alterations in the CD4 memory response. We will immunize adoptively transferred naive Tg+ CD4 T cells from young/old mice and analyze the recovered memory cells for phenotype, frequency and their ability to differentiate into effector cells upon restimulation with antigen in vitro. Memory effector cell function will also be evaluated. We will determine the contribution by the aged environment on the generation of memory responses by transferring young Tg+ CD4 T cells to young/aged hosts. if responses are diminished with aging, we will determine if the addition of IL-2 or inflammatory cytokines restores responsiveness.
In Aim 3 we will determine if alterations in the longevity of CD4 T cells in the periphery of the aged contribute to the deficiency in IL-2 production. Using adoptive cell transfer we will determine differences in T cell longevity, turnover and expression of survival/apoptotic factors. We will determine the contribution by the age of the host on longevity/turnover/survival. We will manipulate conditions such that we may induce young cells to """"""""age"""""""" (i.e., increased longevity) and vice versa, and determine if these manipulations induce alterations in antigen specific function (i.e., IL-2 production).
| Linton, Phyllis-Jean; Li, Shaokang P; Zhang, Yu et al. (2005) Intrinsic versus environmental influences on T-cell responses in aging. Immunol Rev 205:207-19 |
| Linton, Phyllis Jean; Dorshkind, Kenneth (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5:133-9 |
| Effros, Rita B; Cai, Zeling; Linton, Phyllis-Jean (2003) CD8 T cells and aging. Crit Rev Immunol 23:45-64 |
| Linton, Phyllis-Jean; Bautista, Beverly; Biederman, Elana et al. (2003) Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo. J Exp Med 197:875-83 |
| Bradley, Linda M; Harbertson, Judith; Biederman, Elana et al. (2002) Availability of antigen-presenting cells can determine the extent of CD4 effector expansion and priming for secretion of Th2 cytokines in vivo. Eur J Immunol 32:2338-46 |
