title: Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis.
abstract: BACKGROUND
  T cells are essential for the development of uveitis and other autoimmune diseases. After initial activation, CD4+ lymphocytes express the co-stimulatory molecule OX40 that plays an important role in T cell proliferation. Cyclin dependent kinase 2 (CdK2) plays a pivotal role in the cell cycle transition from G1 to S phase. In addition, recent research has implicated CdK2 in T cell activation. Thus, we sought to test the immunosuppressive effect of roscovitine, a potent CdK2 inhibitor, on CD4+ T cell activation, proliferation, and function.
  
  
  METHODS
  Mouse CD4+ T cells were activated by anti-CD3 and anti-CD28 antibodies. The expression of OX40, CD44, and CdK2 were analyzed by flow cytometry. In addition, cell cycle progression and apoptosis of control and roscovitine-treated T lymphocytes were measured by BrdU incorporation and annexin V assay, respectively. Furthermore, the immunoregulatory effect of roscovitine was evaluated in both ovalbumin-induced uveitis and experimental autoimmune uveitis (EAU) models.
  
  
  RESULTS
  In this study, we found that T cell activation induced OX40 expression. Cell cycle analysis showed that more CD4+OX40+ cells entered S phase than OX40- T cells. Concurrently, CD4+OX40+ cells had a higher level of CdK2 expression. Roscovitine treatment blocked activated CD4+ cells from entering S phase. In addition, roscovitine not only reduced the viability of CD4+ lymphocytes but also suppressed T cell activation and cytokine production. Finally, roscovitine significantly attenuated the severity of T cell-dependent, OX40-enhanced uveitis.
  
  
  CONCLUSIONS
  These results implicate CdK2 in OX40-augmented T cell response and expansion. Furthermore, this study suggests that roscovitine is a novel, promising, therapeutic agent for treating T cell-mediated diseases such as uveitis.
authors.affiliation: Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, United States of America ; Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Konstantin S
authors.initials: KS
authors.lastname: Leskov
authors.forename: Xiumei
authors.initials: X
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Duan
authors.forename: Gary L
authors.initials: GL
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Hall
authors.forename: James T
authors.initials: JT
authors.lastname: Rosenbaum
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D000077546:Roscovitine; D016196:S Phase / Q000187:drug effects; D014605:Uveitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D007155:Immunologic Factors; D047428:Protein Kinase Inhibitors; D011687:Purines; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D000077546:Roscovitine; D010047:Ovalbumin; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2