Title: The cyclin-dependent kinase inhibitor p21 mediates dendritic cell maturation and allospecific T cell priming
Abstract: Dendritic cells (DCs) have received increasing attention as a tool to manipulate the immune response following transplantation. DC maturational state has been shown to be one of the factors critical to allospecific T cell priming. We have previously shown that increased expression of the cyclin-dependent kinase inhibitor p21 in cardiac allografts can prolong allograft survival. The specific effect of p21 on DC maturation remains to be defined. We hypothesized that p21-deficient DC would mature more readily and therefore induce increased allospecific T cell priming. To test this hypothesis, we cultured bone marrow derived DC from p21 knockout (p21-/- on B6129 background) or wild type (wt) mice in the presence of GM-CSF to maintain DC in a relatively immature state. FACS analysis was performed to assess DC markers of maturation (MHC class II, CD80, CD86, and CD40). Allospecific T cell priming was determined by performing mixed lymphocyte reactions (MLR) using DC as stimulators of BALB/c responder splenocytes. ELISPOT and 3H-thymidine incorporation assays were used to determine T cell cytokine production and T cell proliferation, respectively, following MLR. DC p21 deficiency increased the surface expression of the co-stimulatory molecules CD80 (45 ± 10% of DC) and CD86 (40 ± 7% of DC) over that of wt (20 ± 4% of DC) and (22 ± 5% of DC), respectively (p < 0.05, n = 4). MHC class II and CD40 surface expression were unchanged. Following a 3 day MLR, p21 -/- DC induced greater allospecific T cell proliferation when compared to wt DC (3541 ± 207 cpm vs. 1909 ± 388 cpm, p < 0.05, n = 4). ELISPOT revealed that p21 -/- DC induced both greater Th1 priming (IFN-gamma producing cells 152 ± 7 in p21 -/- DC vs 90 ± 19 in wt DC, p < 0.05, n = 3) and Th2 priming (IL-4 producing cells 142 ± 15 in p21 -/- DC vs 92 ± 7 in wt DC, p < 0.05) following MLR. In conclusion, p21 deficiency increases DC maturation and subsequently augments the ability of DC to induce allospecific T cell priming. Thus, p21 manipulation may serve as an important modality to alter DC maturational state and thus inhibit allospecific T cell priming following transplantation.
Publication Year: 2003
Publication Date: 2003-10-01
Language: en
Type: article
Indexed In: ['crossref']
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