Reactome | Co-inhibition by CTLA4

Co-inhibition by CTLA4

Stable Identifier

R-HSA-389513

Type

Pathway

Species

Homo sapiens

Synonyms

CTLA4 inhibitory signaling

ReviewStatus

5/5

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Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an immune checkpoint molecule predominantly expressed on the surface of activated T cells and regulatory T (Treg) cells. It plays a critical role in inhibiting T-cell activation and maintaining immune homeostasis (Alegre et al. 2001). After acctivation of T lymphocytes through their antigen receptor (TCR) induces the upregulation of CTLA-4 expression. CTLA-4 engagement alongside TCR activation inhibits T cell responses through two primary mechanisms: competing with CD28 for B7 binding to reduce costimulation, and delivering a negative signal directly into the T cells. It has been reported that phosphotyrosine-dependent recruitment of the SHP-2 phosphatase to CTLA-4 inhibits T cell activation and expansion by dephosphorylation of CD3/TCR chains.
CTLA-4 inhibits T cell activation through several mechanisms, including the reduction of IL-2 production and expression, as well as by arresting T cells in the G1 phase of the cell cycle (Greenwald et al. 2002). This checkpoint molecule not only impacts the T cells that express it but also exerts a dominant regulatory influence on the proliferation of other T cells. This ability to limit the proliferation of surrounding T cells is crucial in preventing autoreactivity and maintaining immune tolerance, ensuring that the immune system does not inadvertently target the body's own tissues.
Due to its ability to modulate immune responses, CTLA-4 has emerged as a significant therapeutic target for managing conditions such as cancer, autoimmune diseases, and transplant rejection (Tivol et al. 1995, Chambers et al. 1997, Rudd and Schneider 2003).

Literature References

PubMed ID	Title	Journal	Year
10374692	CD28/CTLA-4 and CD80/CD86 families: signaling and function Slavik, JM, Hutchcroft, JE, Bierer, BE	Immunol Res	1999
12876557	Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling Rudd, CE, Schneider, H	Nat Rev Immunol	2003
16551244	A molecular perspective of CTLA-4 function Teft, WA, Kirchhof, MG, Madrenas, J	Annu Rev Immunol	2006
16598076	The multifunctional GIT family of proteins Hoefen, RJ, Berk, BC	J Cell Sci	2006
11905831	T-cell regulation by CD28 and CTLA-4 Alegre, ML, Frauwirth, KA, Thompson, CB	Nat Rev Immunol	2001
24705298	Protein kinase C-η controls CTLA-4-mediated regulatory T cell function Kong, KF, Fu, G, Zhang, Y, Yokosuka, T, Casas, J, Canonigo-Balancio, AJ, Becart, S, Kim, G, Yates, JR, Kronenberg, M, Saito, T, Gascoigne, NR, Altman, A	Nat Immunol	2014