Abstract 9628: Krüppel-like Factor-10 Serves as a T cell Anti-Aging Factor in Organ Transplantation
The response of T cells to mitogens wanes with normal aging. Previous work has implicated cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in the hyporesponsiveness of T cells in the elderly; such reduced activation could impact allograft survival. Conversely, Krüppel-like factor 10 (KLF10) is a transcription factor involved in T-cell activation. This study investigated whether KLF10 participates in age-related diminution in cardiac allograft rejection, using KLF10-deficient mice (KLF10-/-).
Methods and Results: Major histocompatibility complex class II (MHC II)-mismatched cardiac allografts showed similar survival when transplanted into young recipients (8-12 week old) of either wild-type (WT) or KLF10-/- strains. In contrast, allografts in older KLF10-/- recipients (20-24 week old) survived an average of only 4.4±2.1 weeks (n=8), compared to >12 weeks (n = 6, p<0.0001) in older WT hosts. At 4 weeks post-transplantation, allografts in older KLF10-/- recipients had significantly higher parenchymal rejection scores (3±0.8, n=6) than did older WT recipients (1.4±0.5, n=7, p <0.005); allografts in older KLF10-/- hosts also had significantly increased allograft accumulation of T cells and macrophages, and significantly increased mRNA levels of IL-6, IFN-γ, TNF-α, MCP-1, IP-10, Mig, and I-TAC compared to WT recipient allografts. Mixed lymphocyte reactions using older KLF10-/- responder cells showed significantly higher reactions compared to WT responders (20-fold), while younger WT and KLF10-/- responders were comparable. WT T cells in older animals expressed significantly higher CTLA-4 levels (4-fold) than did those in young mice, while old KLF10-/- mice expressed lower CTLA-4 levels and higher levels of CD28 expression compared to young KLF10-/- mice. Cardiac allografts of KLF10-/- young host adoptively receiving older KLF10-/- T cells significantly augmented parenchymal rejection with increased inflammatory cell infiltration compared to young KLF10-/- T cell transferred recipient allografts.
Conclusion: The absence of KLF10 in older recipient T cells markedly increased effector T-cell activation and exacerbated allograft rejection. Thus, KLF10 regulates age-dependent immune responses in cardiac transplantation.
- © 2011 by American Heart Association, Inc.