Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation.
BACKGROUND
The cyclin-dependent kinase (cdk) inhibitor p21 inhibits cellular proliferation of many cell types, including T cells. Autoimmune models, however, have yielded conflicting results regarding the role of cdk inhibitors and T-cell function. The role of p21 in T-cell function after transplantation has not been investigated directly. We hypothesized that p21 plays an important role in alloantigen-driven responses in vitro in mixed lymphocyte cultures (MLC) and in vivo using the heterotopic murine cardiac allograft model.


METHODS
Wild type (WT) and p21-deficient (p21-/-) mice were used as recipients, and the effects of p21 overexpression were assessed by transplanting p21 adenoviral-transfected cardiac allografts. Enzyme-linked immunospot (ELISPOT) and 3H-thymidine incorporation were used to evaluate for T-cell priming and proliferation in vitro, whereas graft histology was evaluated for rejection.


RESULTS
When stimulated with alloantigens in vitro, splenocytes from p21-/- mice mounted enhanced proliferative responses and decreased Th2 responses relative to their WT counterparts. No differences in Th1 responses were noted when p21-/- cells were stimulated with alloantigens in vitro; however, after cardiac transplantation, Th1 responses were enhanced in p21-/- recipients relative to WT mice. This enhanced in vivo Th1 response was associated with exacerbated graft rejection in p21-/- recipients. Interestingly, p21 transfection of WT allografts inhibited graft rejection and Th1 priming.


CONCLUSIONS
p21 controls the intensity of the immune response posttransplantation, with overexpression inhibiting allograft rejection. Our data demonstrate that p21 controls T-cell priming and suggest that p21 and other cdk inhibitors may serve as potential targets for therapeutic manipulation of alloimmune responses.
Welling
Theodore H
TH
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Mich, USA. twelling@umich.edu
Lu
Guanyi
G
Csencsits
Keri
K
Wood
Sherri C
SC
Jarvinen
Lamis
L
Bishop
D Keith
DK
D000818:Animals; D041702:BALB 3T3 Cells; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D014162:Transfection; D014181:Transplantation Immunology / Q000276:immunology
D050759:Cyclin-Dependent Kinase Inhibitor p21; D007519:Isoantigens