ABSTRACT
Study of immune senescence is complicated by low numbers of antigen-specific lymphocytes, particularly naïve T (Tn)cells which disappear with aging. Although T cell receptor (TCR) transgenic mice facilitate aging research, their large number of Ag-specific T cells renders their T cell pool abnormal, precluding normal in vivo immunity. To create a physiologically relevant model with measurable numbers of TCR transgenic CD4+ T cells in the context of normal lymphocytes, mixed (DO11.10+BALB/c) bone marrow (BM) chimeras were constructed. As found in normal mice, the total number of transgenic T cells and the Tn:memory T cell ratio declined with the aging of the BM chimeras. Although these shifts in T cell subsets were evident in both the lymph nodes and the spleen (SP), they were more pronounced in the SP. Unlike DO11.10 mice, transgenic T cells in the chimera acquired an effector/memory phenotype upon antigen challenge. These results reveal a pliable model to study the impact of the constriction of the Tn cell repertoire upon optimal vaccine responses in the elderly.
Subject(s)
Aging/immunology , T-Lymphocyte Subsets/immunology , Transplantation Chimera/immunology , Adoptive Transfer , Animals , Bone Marrow/immunology , Bone Marrow Transplantation , Flow Cytometry , Fluorescent Antibody Technique , Lymph Nodes/cytology , Lymph Nodes/immunology , Mice , Mice, Inbred BALB C , Mice, Transgenic , Spleen/cytology , Spleen/immunologyABSTRACT
The impact of CD28 ligation upon CD4+ and CD8+ T lymphocyte proliferation and cytokine production was assessed. Although costimulation increased the proliferative response of both T cell subsets, cytokine production was most markedly increased in the CD4+ subset, as evidenced by a 40-fold increase in interleukin-2 (IL-2), a 14-fold increase in interleukin-3 (IL-3) and 5-fold increases in interferon gamma and GM-colony-stimulating factor (CSF) production. The CD8+ T cell response to CD28 ligation was less marked, maxima being a 5-fold increase in IL-2 production and 2-fold increases in IL-3 and GM-CSF production. Resolution of CD4+ and CD8+ T cells into their CD44lo (naïve) and CD44hi (memory/effector) subsets revealed that naive CD4+ T cells were the most CD28-responsive subsets. CD28-mediated costimulation promotes distinct differentiation programs in CD4+ versus CD8+ T cells.
Subject(s)
CD28 Antigens/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Cytokines/metabolism , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cell Division/immunology , Cytokines/genetics , Hyaluronan Receptors/immunology , Hyaluronan Receptors/metabolism , Male , Mice , Mice, Inbred BALB C , RNA, Messenger/metabolism , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Time FactorsABSTRACT
T cell proliferative responses decrease with age, but the mechanisms responsible are unknown. We examined the impact of age on memory and naive CD4(+) T cell entry and progression through the cell cycle using acridine orange to identify cell cycle stage. For both subsets, fewer stimulated cells from old donors were able to enter and progress through the first cell cycle, with an increased number of cells arrested in G(0) and fewer cells in post G(0) phases. The number of dead cells as assessed by sub-G(0) DNA was also significantly greater in the old group. CD4(+) T cells from old mice also exhibited a significant reduction in clonal history as assessed by CFSE staining. This was associated with a significant decline in cyclin D2 mRNA and protein. We propose that decreases in cyclin D2 are at least partially responsible for the proliferative decline found in aged CD4(+) T cells.
