CTLA-4 regulates cell cycle progression during a primary immune response.
Engagement of CTLA-4 is critical for inhibiting T cell immune responses. Recent studies have shown that CTLA-4 plays a key role in regulating peripheral T cell tolerance. It has been suggested that one mechanism by which CTLA-4 performs this function is by regulating cell cycle progression. Here, we investigate in depth the role of CTLA-4 in regulating cell cycle progression in naive T cells by comparing the immune responses in the absence or presence of CTLA-4. In the absence of CLTA-4, T cells exhibit marked increases in T cell proliferation, IL-2 mRNA and protein secretion, and cells cycling in the S and G2-M phase. Analyses of cyclins, cyclin-dependent kinases, and cell cycle inhibitors involved in the transition from the G1 to S phase reveal that cell cycle progression is prolonged in the absence of CTLA-4. This is due to the early exit from the G1 phase, entry into the S phase, and prolonged S phase period. Re-expression of the cell cycle inhibitor p27(kip1) is delayed in the absence of CTLA-4. These studies demonstrate that the B7 : CTLA-4 pathway exerts its major effects on T cell immune responses via regulation of the cell cycle.
Greenwald
Rebecca J
RJ
Immunology Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
Oosterwegel
Mariette A
MA
van der Woude
Diane
D
Kubal
Anup
A
Mandelbrot
Didier A
DA
Boussiotis
Vassiliki A
VA
Sharpe
Arlene H
AH
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D002453:Cell Cycle / Q000276:immunology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D016213:Cyclins / Q000096:biosynthesis; D005260:Female; D016193:G1 Phase / Q000276:immunology; D018796:Immunoconjugates; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016196:S Phase / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; C556707:Ctla4 protein, mouse; D016213:Cyclins; D018796:Immunoconjugates; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069594:Abatacept; D018844:Cyclin-Dependent Kinases