Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Article metrics


Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)—which encodes a vital negative regulatory molecule of the immune system—as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1?kb 3′ region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Association of the CD28CTLA4ICOS region with Graves' disease.
Figure 2: Expression of the human CTLA-4 mRNA isoforms correlates with genotype.
Figure 3: Sequence, splicing and expression of Ctla4 in NOD mice and congenic strains.


  1. 1

    Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S. & Hirschhorn, J. N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nature Genet. 33, 177–182 (2003)

  2. 2

    Dahlman, I. et al. Parameters for reliable results in genetic association studies in common disease. Nature Genet. 30, 149–150 (2002)

  3. 3

    Lesage, S. & Goodnow, C. C. Organ-specific autoimmune disease: a deficiency of tolerogenic stimulation. J. Exp. Med. 194, F31–F36 (2001)

  4. 4

    Finger, E. & Bluestone, J. When ligand becomes receptor-tolerance via B7 signaling on DCs. Nature Immunol. 3, 1056–1057 (2002)

  5. 5

    Egen, J. G., Kuhns, M. S. & Allison, J. P. CTLA-4: new insights into its biological function and use in tumour immunotherapy. Nature Immunol. 3, 611–618 (2002)

  6. 6

    Nistico, L. et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Hum. Mol. Gen. 5, 1075–1080 (1996)

  7. 7

    Marron, M. P. et al. Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33. Diabetes 49, 492–499 (2000)

  8. 8

    Allahabadia, A. et al. The MHC class II region, CTLA-4 gene and ophthalmopathy in patients with Graves' disease. Lancet 358, 984–985 (2001)

  9. 9

    Kristiansen, O. P., Larsen, Z. M. & Pociot, F. CTLA-4 in autoimmune diseases—a general susceptibility gene to autoimmunity? Genes Immun. 1, 170–184 (2000)

  10. 10

    Colucci, F., Bergman, M., Penha-Goncalves, C., Cilio, C. M. & Holmberg, D. Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region. Proc. Natl Acad. Sci. USA 94, 8670–8674 (1997)

  11. 11

    Hill, N. J. et al. The NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans. Diabetes 49, 1744–1747 (2000)

  12. 12

    Lamhamedi-Cherradi, S. E. et al. Further mapping of the Idd5.1 locus for autoimmune diabetes in NOD mice. Diabetes 50, 2874–2878 (2001)

  13. 13

    Sharpe, A. H. & Freeman, G. J. The B7-CD28 superfamily. Nature Rev. Immunol. 2, 116–126 (2002)

  14. 14

    Grohmann, U. et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunol. 3, 1097–1101 (2002)

  15. 15

    Lin, H. et al. Cytotoxic T lymphocyte antigen 4 (CTLA4) blockade accelerates the acute rejection of cardiac allografts in CD28-deficient mice: CTLA4 can function independently of CD28. J. Exp. Med. 188, 199–204 (1998)

  16. 16

    Chikuma, S., Imboden, J. & Bluestone, J. A. Negative regulation of T cell receptor-lipid raft interaction by cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 197, 129–135 (2003)

  17. 17

    Gabriel, S. B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002)

  18. 18

    Cordell, H. J. & Clayton, D. G. A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am. J. Hum. Genet. 70, 124–141 (2002)

  19. 19

    Magistrelli, G. et al. A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur. J. Immunol. 29, 3596–3602 (1999)

  20. 20

    Oaks, M. K. & Hallett, K. M. Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease. J. Immunol. 164, 5015–5018 (2000)

  21. 21

    Oaks, M. K. et al. A native soluble form of CTLA-4. Cell Immunol. 201, 144–153 (2000)

  22. 22

    Kaijzel, E. L. et al. Allele-specific quantification of tumour necrosis factor alpha (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals. Genes Immun. 2, 135–144 (2001)

  23. 23

    Lynch, K. W. & Weiss, A. A CD45 polymorphism associated with multiple sclerosis disrupts an exonic splicing silencer. J. Biol. Chem. 276, 24341–24347 (2001)

  24. 24

    Zheng, Z.-M., He, P.-J. & Baker, C. Function of a bovine papillomavirus type 1 exonic splicing suppressor requires a suboptimal upstream 3′ splice site. J. Virol. 73, 29–36 (1999)

  25. 25

    Asano, M., Toda, M., Sakguchi, N. & Sakaguchi, S. Autoimmune disease as a consequence of developmental abnormality of a T cell population. J. Exp. Med. 184, 387–396 (1996)

  26. 26

    Manzotti, C. et al. Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory cells. Eur. J. Immunol. 32, 2888–2896 (2002)

  27. 27

    Maloy, K. J. et al. CD4 + CD25 + T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003)

  28. 28

    Sakaguchi, S. Control of immune responses by naturally arising CD4(+ ) regulatory T cells that express Toll-like receptors. J. Exp. Med. 197, 397–401 (2003)

  29. 29

    Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003)

  30. 30

    Kaufman, K. A. et al. The CTLA-4 gene is expressed in placental fibroblasts. Mol. Hum. Reprod. 5, 84–87 (1999)

  31. 31

    Huang, D., Giscombe, R., Zhou, Y., Pirskanen, R. & Lefvert, A. Dinucleotide repeat expansion in the CTLA-4 gene leads to T cell hyper-reactivity via the CD28 pathway in myasthenia gravis. J. Neuroimmunol. 105, 69–77 (2000)

  32. 32

    Kouki, T. et al. CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease. J. Immunol. 165, 6606–6611 (2000)

  33. 33

    Maurer, M. et al. A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics 54, 1–8 (2002)

  34. 34

    Magistrelli, G. et al. Identification of three alternatively spliced variants of human CD28 mRNA. Biochem. Biophys. Res. Commun. 259, 34–37 (1999)

  35. 35

    Hanawa, H. et al. A novel costimulatory signalling in human T lymphocytes by a splice variant of CD28. Blood 99, 2138–2145 (2002)

  36. 36

    Howard, T. et al. Fine mapping of an IgE-controlling gene on chromosome 2q: analysis of CTLA4 and CD28. J. Allergy Clin. Immunol. 110, 743–751 (2002)

  37. 37

    Todd, J. A. A protective role of the environment in the development of type 1 diabetes? Diabetic Med. 8, 906–910 (1991)

  38. 38

    Strachan, D. P. Hay fever, hygiene, and household size. Br. Med. J. 299, 1259–1260 (1989)

  39. 39

    Bain, S. C., Todd, J. A. & Barnett, A. H. The British Diabetic Association — Warren Repository. Autoimmunity 7, 83–85 (1990)

  40. 40

    Lernmark, A. et al. Family cell lines available for research. Am. J. Hum. Genet. 47, 1028–1030 (1990)

  41. 41

    Patterson, C. C., Carson, D. J. & Hadden, D. R. Epidemiology of childhood IDDM in Northern Ireland 1989–1994: low incidence in areas with highest population density and most household crowding. Northern Ireland Diabetes Study Group. Diabetologia 39, 1063–1069 (1996)

  42. 42

    Tuomilehto, J. et al. Epidemiology of childhood diabetes mellitus in Finland—background of a nationwide study of type 1 (insulin-dependent) diabetes mellitus. The Childhood Diabetes in Finland (DiMe) Study Group. Diabetologia 35, 70–76 (1992)

  43. 43

    Mein, C. A. et al. Evaluation of single nucleotide polymorphism typing with invader on PCR amplicons and its automation. Genome Res. 10, 330–343 (2000)

  44. 44

    Olivier, M. et al. High-throughput genotyping of single nucleotide polymorphisms using new biplex invader technology. Nucleic Acids Res. 30, e53 (2002)

  45. 45

    Clayton, D. in Handbook of Statistical Genetics (eds Balding, D., Bishop, M. & Cannings, C.) 519–540 (Wiley, Chichester, 2001)

  46. 46

    Spielman, R., McGinnis, R. & Ewens, W. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516 (1993)

Download references


We thank the Juvenile Diabetes Research Foundation (JDRF), the Wellcome Trust, NovoNordisk, Novo Nordisk Foundation, the Academy of Finland, The Sigrid Juselius Foundation, Diabetes UK and the Medical Research Council for financial support. H.U. was a Wellcome Trust Travelling Fellow and R.N. is a West Midlands Regional Health Authority Sheldon Medical Research Fellow. The availability of NOD congenic mice through the Taconic Farms Emerging Models Program has been made possible and is supported by grants from the Merck Genome Research Institute, NIAID and the JDRF. We gratefully acknowledge the participation of all patients, controls and family members, including provision of samples from T1D families from the Human Biological Data Interchange and Diabetes UK repositories, and sample collections by The Norwegian Study Group for Childhood, preparation of manuscript materials by J. Brown and T. Thorn, and review of the manuscript by C. Rudd, C. Nathan, M. Bobrow, P. Lyons, R. Glynne, C. Goodnow, J. Trowsdale, N. Proudfoot, T. Merriman, N. Hastie and D. Sansom.

Author information

Correspondence to Linda S. Wicker or John A. Todd.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ueda, H., Howson, J., Esposito, L. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003) doi:10.1038/nature01621

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.