CTLA-4

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a member of the CD28 superfamily and is a negative regulator of T cell-mediated immune responses. CTLA-4 exhibits cell surface and intracellular constitutive expression on memory T-cells and at a low level by T-regulatory cells (Tregs; 2-4% of circulating CD4+ T cells) (1,2). CTLA-4 primarily inactivates T-cell activity by competing with the CD28 costimulatory molecule (3). CD28 and CTLA-4 share the identical ligands of CD80 and CD86 on antigen-presenting cells; and thus CTLA-4 competes with CD28 function in T-cell survival, proliferation, and recruitment (3,4). In particular, CTLA-4 down-modulates CD4+ helper T-cell activity and enhances Treg immunosuppressive functions (5,6).

CTLA-4 has been shown to play a role in human diseases (1). CTLA-4 acts as a physiological brake on the activated immune system in order to maintain immune homeostasis. Several suppressive mechanisms for T-cell functions have been attributed to CTLA-4. FDA approved Ipilimumab (IgG1 isotype), a monoclonal antibody to CTLA-4, was the first immunotherapeutic drug directed toward CTLA-4 inhibition to demonstrate overall survival benefit in metastatic melanoma (1,7). Another CTLA-4 inhibitor, tremelimumab (IgG2 isotype), has also proven successful in metastatic melanoma and other malignancies (1,7).

Specifications

1. Buchbinder EI, McDermott DF. Cytotoxic T-lymphocyte antigen-4 blockade in melanoma. Clinical Therapeutics. 2015; 37:755-63.
2. Baecher-Allan C, et al. Human CD4+CD25+ regulatory T cells. Semin Immunol. 2004 Apr; 16(2):89-98.
3. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992; 71:1065-8.
4. Azuma M, et al. B70 antigen is a second ligand for CTLA-4 and CD28. Nature 1993; 366:76-9.
5. Hathcock KS, et al. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science. 1993; 262:905-7.
6. Wing K, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008; 322:271-5.
7. Shin DS, Ribas A. The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s next? Curr Opin Immunol. 2015; 33:23- 35.
8. Center for Disease Control Manual. Guide: Safety Management, NO. CDC-22, Atlanta, GA. April 30, 1976 “Decontamination of Laboratory Sink Drains to Remove Azide Salts.”
9. Clinical and Laboratory Standards Institute (CLSI). Protection of Laboratory Workers from Occupationally Acquired Infections; Approved Guideline-Fourth Edition CLSI document M29-A4 Wayne, PA 2014.