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

Eur J Immunol. 2002 Feb;32(2):366-73. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • CTLA-4 Antigen
  • Cell Cycle / immunology*
  • Cell Cycle Proteins / metabolism
  • 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
  • S Phase / immunology
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tumor Suppressor Proteins / metabolism


  • Antigens, CD
  • Antigens, Differentiation
  • B7-1 Antigen
  • B7-2 Antigen
  • CTLA-4 Antigen
  • Cd86 protein, mouse
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Ctla4 protein, mouse
  • Cyclins
  • Immunoconjugates
  • Interleukin-2
  • Membrane Glycoproteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Abatacept
  • Cyclin-Dependent Kinases