CTLA-4, an essential immune-checkpoint for T-Cell activation

Shunsuke Chikuma

Research output: Chapter in Book/Report/Conference proceedingChapter

109 Citations (Scopus)


The response of peripheral T lymphocytes (T cell) is controlled by multiple checkpoints to avoid unwanted activation against self-tissues. Two opposing costimulatory receptors, CD28 and CTLA-4, on T cells bind to the same ligands (CD80 and CD86) on antigen-presenting cells (APCs), and provide positive and negative feedback for T-cell activation, respectively. Early studies suggested that CTLA-4 is induced on activated T cells and binds to CD80/CD86 with much stronger affinity than CD28, providing a competitive inhibition. Subsequent studies by many researchers revealed the more complex mode of T-cell inhibition by CTLA-4. After T-cell activation, CTLA-4 is stored in the intracellular vesicles, and recruited to the immunological synapse formed between T cells and APCs, and inhibits further activation of T cells by blocking signals initiated by T-cell receptors and CD28. CTLA-4-positive cells can also provide cell-extrinsic regulation on other autoreactive T cells, and are considered to provide an essential regulatory mechanism for FoxP3+ regulatory T cells. Genetic deficiency of CTLA-4 leads to CD28-mediated severe autoimmunity in mice and humans, suggesting its function as a fundamental brake that restrains the expansion and activation of self-reactive T cells. In cancer, therapeutic approaches targeting CTLA-4 by humanized blocking antibodies has been demonstrated to be an effective immunotherapy by reversing T-cell tolerance against tumors. This chapter introduces CTLA-4 biology, including its discovery and mechanism of action, and discusses questions related to CTLA-4.

Original languageEnglish
Title of host publicationCurrent Topics in Microbiology and Immunology
PublisherSpringer Verlag
Number of pages28
Publication statusPublished - 2017

Publication series

NameCurrent Topics in Microbiology and Immunology
ISSN (Print)0070-217X
ISSN (Electronic)2196-9965

ASJC Scopus subject areas

  • Immunology and Allergy
  • Microbiology
  • Immunology
  • Microbiology (medical)


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