CTLA-4: Hiding in Plain Sight

Over a decade ago, human cytotoxic T lymphocyte-associated molecule 4 (CTLA-4; also known as CD152) was identified and described as an immunoglobulin superfamily member upregulated upon lymphocyte activation.1 CTLA-4 is homologous to the previously identified CD28 molecule. The two are similar in genomic location (very closely linked at human chromosome 2q33), gene organization (four exons of similar sizes), sequence (approximately 30% amino acid identity), protein structure (single extracellular V-like immunoglobin, transmembrane, and intracellular domains), and expression (lymphocyte-restricted).2 Both CTLA-4 and CD28 form homodimers and interact with their ligands, B7-1 and B7-2, to participate in one of the dominant co-stimulatory pathways that governs T cell activation. However, there are critical differences in the function of CTLA-4 and CD28 that are important, particularly for T cell responsiveness and tolerance.3

Figure 1. Graphic representation of the physical location of SNPs and their allelic frequencies within the approximately 400 kb region that includes CD28, CTLA-4, and ICOS genes and has been associated with susceptibility to organ-specific autoimmune disease. [Note: figure adapted from Ueda, H. et al. (2003) Nature 423:506.]

CD28 is expressed by both resting and activated T cells. When bound by either B7-1 or B7-2 expressed by antigen presenting cells (APC), CD28 offers a co-stimulatory signal that augments the T cell response to TCR binding of APC-displayed MHCII/antigen complexes. In contrast, CTLA-4 is not expressed on the surface of resting T cells. Rather, it moves to the surface upon CD28 stimulation, binds the same B7-1 and B7-2 ligands with much greater affinity, and transduces an inhibitory signal to temper the T cell response.3,4 The net immune response by T cells results from the balance of immunity-producing CD28-mediated activation and tolerance-generating CTLA-4-mediated inhibition.4 Disruption of the delicate balance between the opposing functions of CD28 and CTLA-4 could lead to immunodeficiencies, or alternatively, excessive immune responses and autoimmunity.5 It is not surprising then, that several independent laboratories have linked the chromosome 2q33 genomic region, containing CD28 and CTLA-4 [and other T cell regulatory genes including ICOS (inducible costimulator)], to organ-specific autoimmune disease susceptibility.3-6 However, auto-immune diseases have an extremely complex heritability pattern and are multifactorial in nature. Therefore, while this region has been associated with organ-specific autoimmune disease susceptibility, the complexity of these diseases have confounded efforts to definitively name specific genes and polymorphisms responsible.5,6

A recent study by Ueda et al. names CTLA-4 as a gene associated with Graves' Disease (GD), Autoimmune Hypothyroidism (AIH), and Type 1 Diabetes (T1D).6 These investigators sequenced the entire 330 kb region containing CD28, CTLA-4, and ICOS, the only functional genes found in the region. On searching the region for single nucleotide polymorphisms (SNPs), 108 were documented in the CTLA-4 3' untranslated region (UTR). A 6.1 kb region at the CTLA-4-proximal 3' UTR was significantly associated with GD, AIH, and T1D (Figure 1). On examination of the molecular effect of polymorphisms in this region, it was observed that mRNA encoding the soluble splice variant of CTLA-4 (sCTLA-4) was reduced significantly in a semi-dominant fashion. These data suggest that the 6.1 kb CTLA-4 3' UTR is important for splicing efficiency and that sCTLA-4 is important for T cell tolerance and prevention of autoimmune diseases including GD, AIH, and T1D.6

Depressed expression of sCTLA-4 in patients with GD, AIH, and T1D was not a complete surprise. In fact, sCTLA-4 supplementation, with the intent of decreasing CD28-mediated costimulation, has been used for some time as an autoimmunity therapy.7,8 These new data linking polymorphisms in the CTLA-4 gene to GD, AIH, and T1D should aid in the exploration of more effective diagnostic and treatment procedures for organ-specific auto-immune diseases.6


  1. Dariavach, P. et al. (1988) Eur. J. Immunol. 18:1901.
  2. Harper, K. et al. (1991) J. Immunol. 147:1037.
  3. Alegre, M.-L. et al. (2001) Nat. Rev. Immunol. 1:220.
  4. Sharpe, A.H. & G.J. Freeman (2002) Nat. Rev. Immunol. 2:116.
  5. Lesage, S. & C.C. Goodnow (2001) J. Exp. Med. 194:F31.
  6. Ueda, H. et al. (2003) Nature 423:506.
  7. Linsley, P.S. et al. (1992) Science 257:792.
  8. Racke, M.K. & R.W. Stuart (2002) Expert Opin. Ther. Targets 6:275.