TY - JOUR
T1 - Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging
AU - Renkema, Kristin R.
AU - Li, Gang
AU - Wu, Angela
AU - Smithey, Megan J.
AU - Nikolich-Žugich, Janko
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Naive T cell responses are eroded with aging. We and others have recently shown that unimmunized old mice lose ≥70% of Agspecific CD8 T cell precursors and that many of the remaining precursors acquire a virtual (central) memory (VM; CD44hi CD62Lhi) phenotype. In this study, we demonstrate that unimmunized TCR transgenic (TCRTg) mice also undergo massive VM conversion with age, exhibiting rapid effector function upon both TCR and cytokine triggering. Age-related VM conversion in TCRTg mice directly depended on replacement of the original TCRTg specificity by endogenous TCRα rearrangements, indicating that TCR signals must be critical in VM conversion. Importantly, we found that VM conversion had adverse functional effects in both old wild-type and old TCRTg mice; that is, old VM, but not old true naive, T cells exhibited blunted TCR-mediated, but not IL-15-mediated, proliferation. This selective proliferative senescence correlated with increased apoptosis in old VM cells in response to peptide, but decreased apoptosis in response to homeostatic cytokines IL-7 and IL-15. Our results identify TCR as the key factor in differential maintenance and function of Ag-specific precursors in unimmunized mice with aging, and they demonstrate that two separate age-related defects - drastic reduction in true naive T cell precursors and impaired proliferative capacity of their VM cousins - combine to reduce naive T cell responses with aging. The Journal of Immunology, 2014, 192: 151-159.
AB - Naive T cell responses are eroded with aging. We and others have recently shown that unimmunized old mice lose ≥70% of Agspecific CD8 T cell precursors and that many of the remaining precursors acquire a virtual (central) memory (VM; CD44hi CD62Lhi) phenotype. In this study, we demonstrate that unimmunized TCR transgenic (TCRTg) mice also undergo massive VM conversion with age, exhibiting rapid effector function upon both TCR and cytokine triggering. Age-related VM conversion in TCRTg mice directly depended on replacement of the original TCRTg specificity by endogenous TCRα rearrangements, indicating that TCR signals must be critical in VM conversion. Importantly, we found that VM conversion had adverse functional effects in both old wild-type and old TCRTg mice; that is, old VM, but not old true naive, T cells exhibited blunted TCR-mediated, but not IL-15-mediated, proliferation. This selective proliferative senescence correlated with increased apoptosis in old VM cells in response to peptide, but decreased apoptosis in response to homeostatic cytokines IL-7 and IL-15. Our results identify TCR as the key factor in differential maintenance and function of Ag-specific precursors in unimmunized mice with aging, and they demonstrate that two separate age-related defects - drastic reduction in true naive T cell precursors and impaired proliferative capacity of their VM cousins - combine to reduce naive T cell responses with aging. The Journal of Immunology, 2014, 192: 151-159.
UR - http://www.scopus.com/inward/record.url?scp=84891060089&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891060089&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1301453
DO - 10.4049/jimmunol.1301453
M3 - Article
AN - SCOPUS:84891060089
SN - 0022-1767
VL - 192
SP - 151
EP - 159
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -