CTLA-4, an Essential Immune-Checkpoint for T-Cell Activation
- 13 September 2017
- book chapter
- other
- Published by Springer Science and Business Media LLC in Current Topics in Microbiology and Immunology
- Vol. 410, 99-126
- https://doi.org/10.1007/82_2017_61
Abstract
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.Keywords
This publication has 101 references indexed in Scilit:
- Endogenous antigen tunes the responsiveness of naive B cells but not T cellsNature, 2012
- Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell-Extrinsic Function of CTLA-4Science, 2011
- Intrinsic and extrinsic control of peripheral T‐cell tolerance by costimulatory molecules of the CD28/ B7 familyImmunological Reviews, 2011
- Improved Survival with Ipilimumab in Patients with Metastatic MelanomaThe New England Journal of Medicine, 2010
- Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunityProceedings of the National Academy of Sciences of the United States of America, 2010
- CTLA-4 suppresses the pathogenicity of self antigen–specific T cells by cell-intrinsic and cell-extrinsic mechanismsNature Immunology, 2009
- SHP‐1 and SHP‐2 in T cells: two phosphatases functioning at many levelsImmunological Reviews, 2009
- CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic toleranceThe Journal of Experimental Medicine, 2009
- Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune diseaseNature, 2003
- Src Family Tyrosine Kinases Associate with and Phosphorylate CTLA-4 (CD152)Biochemical and Biophysical Research Communications, 1998