Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy

J Clin Invest. 2001 Sep;108(6):895-903. doi: 10.1172/JCI13220.


Primary T cell proliferative responses to TCR ligation plus CD28 costimulation are surprisingly heterogeneous. Many cells that enter G1 fail to progress further through the cell cycle, and some of these cells subsequently fail to divide upon restimulation, even in the presence of IL-2. Such IL-2-refractory anergy is distinct from the IL-2-reversible anergy induced by TCR occupancy in the absence of CD28 costimulation. Here, we focus on the contributions of cell cycle progression and costimulatory (CD28/CTLA-4) signals in the regulation of anergy. We show that CD28 costimulation is not sufficient for anergy avoidance and that activated T cells must progress through the cell cycle in order to escape anergy. Induction of this "division-arrest" form of anergy requires CTLA-4 signaling during the primary response. Also, cell division per se is not sufficient for anergy avoidance: the few T cells that undergo multiple rounds of cell division during overt CD28 costimulatory blockade do not escape the ultimate induction of clonal anergy. Anergy avoidance by primary T cells is thus a multistep process: in order to participate in a productive immune response, an individual T cell activated through its antigen receptor must receive CD28 costimulation and progress through the cell cycle. Anergy may be induced either through a combination of CTLA-4 signaling and the failure of cell cycle progression, or through a proliferation-independent mechanism in which TCR ligation occurs in the absence of CD28.

Publication types

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

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / immunology*
  • CD28 Antigens / immunology*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CTLA-4 Antigen
  • Cell Cycle
  • Cell Cycle Proteins / metabolism
  • Clonal Anergy*
  • Cyclin-Dependent Kinase Inhibitor p27
  • Female
  • Humans
  • Immunoconjugates*
  • In Vitro Techniques
  • Interleukin-2 / pharmacology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Tumor Suppressor Proteins*


  • Antigens, CD
  • Antigens, Differentiation
  • CD28 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Interleukin-2
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Abatacept