CD28 and CTLA-4 Have Opposing Effects on the Response of T Cells to Stimulation

J Exp Med. 1995 Aug 1;182(2):459-65. doi: 10.1084/jem.182.2.459.

Abstract

The importance of the B7/CD28/CTLA-4 molecules has been established in studies of antigen-presenting cell-derived B7 and its interaction with the T cell costimulatory molecule CD28. CTLA-4, a T cell surface glycoprotein that is related to CD28, can also interact with B7-1 and B7-2. However, less is known about the function of CTLA-4, which is expressed at highest levels after activation. We have generated an antibody to CTLA-4 to investigate the consequences of engagement of this molecule in a carefully defined system using highly purified T cells. We show here that the presence of low levels of B7-2 on freshly explanted T cells can partially inhibit T cell proliferation, and this inhibition is mediated by interactions with CTLA-4. Cross-linking of CTLA-4 together with the TCR and CD28 strongly inhibits proliferation and IL-2 secretion by T cells. Finally, results show that CD28 and CTLA-4 deliver opposing signals that appear to be integrated by the T cell in determining the response to activation. These data strongly suggest that the outcome of T cell antigen receptor stimulation is regulated by CD28 costimulatory signals, as well as inhibitory signals derived from CTLA-4.

Publication types

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

MeSH terms

  • Abatacept
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antigens, CD
  • Antigens, Differentiation / physiology*
  • B7-1 Antigen / physiology*
  • CD28 Antigens / physiology*
  • CD3 Complex / physiology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CTLA-4 Antigen
  • Immunoconjugates*
  • Lymphocyte Activation*
  • Lymphokines / biosynthesis
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Signal Transduction

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation
  • B7-1 Antigen
  • CD28 Antigens
  • CD3 Complex
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Lymphokines
  • Abatacept