CTLA‐4 regulates cell cycle progression during a primary immune response

• Published in: European journal of immunology 2002-02, Vol.32 (2), p.366-373
• Main Authors: Greenwald, Rebecca J., Oosterwegel, Mariette A., van der Woude, Diane, Kubal, Anup, Mandelbrot, Didier A., Boussiotis, Vassiliki A., Sharpe, Arlene H.
• Format: Article
• Language: English
• Subjects: Abatacept; Animals; Antigens, CD - genetics; Antigens, CD - physiology; Antigens, Differentiation - genetics; Antigens, Differentiation - physiology; B7-1 Antigen - genetics; B7-1 Antigen - physiology; B7-2 Antigen; Cell cycle; Cell Cycle - immunology; Cell Cycle Proteins - metabolism; Costimulation; CTLA-4 Antigen; CTLA-4 protein; CTLA‐4; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases - biosynthesis; Cyclins - biosynthesis; Female; G1 Phase - immunology; Immunoconjugates; In Vitro Techniques; Interleukin-2 - biosynthesis; Lymphocyte Activation; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Knockout; p27kip1; S Phase - immunology; T lymphocyte; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor Suppressor Proteins - metabolism
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/1521-4141(200202)32:2<366::AID-IMMU366>3.0.CO;2-5

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 suggestedthat 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 p27kip1 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.