Superantigens (SAgs) are microbial products that have the ability to promote massive activation of immune cells, leading to the release of inflammatory mediators that can ultimately result in hypotension, shock, organ failure and death. They achieve this by simultaneously binding and activating major histocompatibility complex class II molecules on antigen‐presenting cells and T‐cell receptors on T lymphocytes bearing susceptible Vβ regions. Why SAgs function in this manner is still not fully understood although it is thought that the resulting Th1 response may divert the immune system from effective microbial clearance and/or result in the cytokine‐mediated suppression and deletion of activated T cells. Many bacterial and viral species have adapted unrelated SAgs and this article will highlight some of the features of this diverse group of molecules, from the ways in which they interact with the host to the association of various SAgs with acute and chronic diseases.

Key Concepts:

  • Superantigens are toxins produced by many pathogenic bacteria and viruses.

  • Superantigens are defined as molecules that bind to the major histocompatibility complex (MHC) class II and active T cells bearing a particular T‐cell receptor beta chain variable (Vβ) domain.

  • Superantigens are implicated in inducing autoimmunity through the activation of autoreactive T cells that express particular Vβ elements.

  • Superantigens are responsible for staphylococcal and streptococcal toxic shock.

  • The superantigens of Staphylococcus aureus are responsible for staphylococcal food poisoning.

  • The endogenous superantigen of the mouse mammary tumour virus (MMTV) causes deletion of T cells bearing a particular Vβ element, amplification of infected B cells and transmission of virus to the offspring.

Keywords: viruses; bacteria; lymphocytes; immunology; MHC; TCR; autoimmunity; toxic shock

Figure 1.

Superantigen presentation. In the centre panel conventional peptide antigens (shown in red) bind to the groove of the major histocompatibility complex (MHC) class II molecules on the surface of antigen‐presenting cells and interact with the hypervariable segments of both the α and β chains of the T‐cell receptor (TCR). Superantigens (shown in orange) associate with MHC class II outside the peptide‐binding groove and concurrently bind the variable region on β chains of susceptible TCR. The left panel shows the possible binding of an endogenously expressed MMTV SAg (which may or may not be extracellularly cleaved) whereas the right side panel shows the interaction of an exogenous SAg with MHC II and the TCR.

Figure 2.

Superantigen structures. (a) The structure of TSST‐1, a representative of the staphylococcal/streptococcal SAg family. The β‐grasp domain (left) is separated from the OB‐fold domain (right) by the central alpha helix (blue). The prosite motifs PS00278 (blue) and PS00277 (red) are highlighted. (b) The structure of YPMa. (c) The structure of MAM as it was determined when bound to MHC II (top) or in its apo form (bottom) as a domain‐swapped dimer.

Figure 3.

Representative response of Vβ8+ T cells to the bacterial superantigen (SEB) in the popliteal lymph nodes. The different phases of the response are depicted by regions (I) amplification; (II) deletion; and (III) anergy.



Abe J, Onimaru M, Matsumoto S et al. (1997) Clinical role for a superantigen in Yersinia pseudotuberculosis infection. Journal of Clinical Investigation 99: 1823–1830.

Altmann D (2005) Antagonist peptide for the treatment of bacterial superantigen toxic shock in a clinical or biowarfare setting. Expert Opinion on Therapeutic Patents 15: 741–743. doi:10.1517/13543776.15.6.741.

Alvarez‐Ossorio L, Johannsen M, Alvarez‐Ossorio R et al. (1998) Cytokine induction by Mycoplasma arthritidis‐derived superantigen (MAS), but not by TSST‐1 or SEC‐3, is correlated to certain HLA‐DR types. Scandinavian Journal of Immunology 47: 43–47.

Arad G, Levy R, Hillman D and Kaempfer R (2000) Superantigen antagonist protects against lethal shock and defines a new domain for T‐cell activation. Nature Medicine 6: 414–421.

Balaban N and Rasooly A (2000) Staphylococcal enterotoxins. International Journal of Food Microbiology 61: 1–10.

Carnoy C, Mullet C, Muller‐Alouf H, Leteurtre E and Simonet M (2000) Superantigen YPMa exacerbates the virulence of Yersinia pseudotuberculosis in mice. Infection and Immunity 68: 2553–2559.

Choi Y, Kappler JW and Marrack P (1991) A superantigen encoded in the open reading frame of the 3′ long terminal repeat of mouse mammary tumour virus. Nature 350: 203–207.

Cole BC, Tuller JW and Sullivan GJ (1987) Stimulation of mouse lymphocytes by a mitogen derived from Mycoplasma arthritidis. VI. Detection of a non‐MHC gene(s) in the E alpha‐bearing RIIIS mouse strain that is associated with a specific lack of T cell responses to the M. arthritidis soluble mitogen. Journal of Immunology 139: 927–935.

Conrad B, Weissmahr RN, Boni J et al. (1997) A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes. Cell 90: 303–313.

Fraser JD and Proft T (2008) The bacterial superantigen and superantigen‐like proteins. Immunological Reviews 225: 226–243.

Fujiwaka H, Igarashi H, Usami H, Tanaka S and Tamura H (1986) Clearance of endotoxin from blood of rabbits injected with staphylococcal toxic shock syndrome toxin‐1. Infection and Immunity 52: 134–137.

Hassan SM and Doolittle BR (2009) A case of Yersinia enterocolitica mimicking Kawasaki disease. Rheumatology (Oxford) 48: 857–858.

Held W, Waanders GA, Shakhov AN et al. (1993) Superantigen‐induced immune stimulation amplifies mouse mammary tumor virus infection and allows virus transmission. Cell 74: 529–540.

Hong‐Geller E, Mollhoff M, Shiflett PR and Gupta G (2004) Design of chimeric receptor mimics with different TcRV beta isoforms Type‐specific inhibition of superantigen pathogenesis. Journal of Biological Chemistry 279: 5676–5684.

Hovde CJ, Marr JC, Hoffmann ML et al. (1994) Investigation of the role of the disulphide bond in the activity and structure of staphylococcal enterotoxin C1. Molecular Microbiology 13: 897–909.

Hsu PN, Wolf Bryant P, Sutkowski N et al. (2001) Association of mouse mammary tumor virus superantigen with MHC class II during biosynthesis. Journal of Immunology 166: 3309–3314.

Kappler JW, Staerz U, White J and Marrack PC (1988) Self‐tolerance eliminates T cells specific for Mls‐modified products of the major histocompatibility complex. Nature 332: 35–40.

Konishi N, Baba K, Abe J et al. (1997) A case of Kawasaki disease with coronary artery aneurysms documenting Yersinia pseudotuberculosis infection. Acta Paediatrica 86: 661–664.

Kotb M (1995) Bacterial pyrogenic exotoxins as superantigens. Clinical Microbiology Reviews 8: 411–426.

Krakauer T (2010) Therapeutic down‐modulators of Staphylococcal superantigen‐induced inflammation and toxic shock. Toxins 2: 1963–1983.

Lafon M (1993) Rabies virus superantigen. Research in Immunology 144: 209–213.

Langley R, Patel D, Jackson N, Clow F and Fraser JD (2010) Staphylococcal superantigen super‐domains in immune evasion. Critical Reviews in Immunology 30: 149–165.

Leung DY (1996) Superantigens related to Kawasaki syndrome. Springer Seminars in Immunopathology 17: 385–396.

Lina G, Bohach GA, Nair SP et al. (2004) Standard nomenclature for the superantigens expressed by Staphylococcus. Journal of Infectious Diseases 189: 2334–2336.

Liu L, Li Z and Guo Y (2010) Crystal structure of the Mycoplasma arthritidis‐derived mitogen in apo form reveals a 3D domain‐swapped dimer. Journal of Molecular Biology 399: 367–376.

Llewelyn M and Cohen J (2002) Superantigens: microbial agents that corrupt immunity. Lancet Infectious Diseases 2: 156–162.

MacDonald HR, Baschieri S and Lees RK (1991) Clonal expansion precedes anergy and death of V beta 8+ peripheral T cells responding to staphylococcal enterotoxin B in vivo. European Journal of Immunology 21: 1963–1966.

MacDonald HR, Schneider R, Lees RK et al. (1988) T‐cell receptor V beta use predicts reactivity and tolerance to Mlsa‐encoded antigens. Nature 332: 40–45.

McCormick JK, Yarwood JM and Schlievert PM (2001) Toxic shock syndrome and bacterial superantigens: an update. Annual Review of Microbiology 55: 77–104.

Mitchell DT, Levitt DG, Schlievert PM and Ohlendorf DH (2000) Structural evidence for the evolution of pyrogenic toxin superantigens. Journal of Molecular Evolution 51: 520–531.

Murzin AG (1993) OB(oligonucleotide/oligosaccharide binding)‐fold: common structural and functional solution for non‐homologous sequences. EMBO Journal 12: 861–867.

Ohmen JD, Barnes PF, Grisso CL, Bloom BR and Modlin RL (1994) Evidence for a superantigen in human tuberculosis. Immunity 1: 35–43.

Perron H, Jouvin‐Marche E, Michel M et al. (2001) Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T‐lymphocyte activation. Virology 287: 321–332.

Proft T and Fraser JD (2007) Streptococcal superantigens. Chemical Immunology and Allergy 93: 1–23.

Saha B, Harlan DM, Lee KP, June CH and Abe R (1996a) Protection against lethal toxic shock by targeted disruption of the CD28 gene. Journal of Experimental Medicine 183: 2675–2680.

Saha B, Jaklic B, Harlan DM et al. (1996b) Toxic shock syndrome toxin‐1‐induced death is prevented by CTLA4Ig. Journal of Immunology 157: 3869–3875.

Schlievert PM (1982) Enhancement of host susceptibility to lethal endotoxin shock by staphylococcal pyrogenic exotoxin type C. Infection and Immunity 36: 123–128.

Sicat J, Sutkowski N and Huber BT (2005) Expression of human endogenous retrovirus HERV‐K18 superantigen is elevated in juvenile rheumatoid arthritis. Journal of Rheumatology 32: 1821–1831.

Stauffer Y, Marguerat S, Meylan F et al. (2001) Interferon‐alpha‐induced endogenous superantigen: a model linking environment and autoimmunity. Immunity 15: 591–601.

Stuart PM, Munn RK, DeMoll E and Woodward JG (1995) Characterization of human T‐cell responses to Yersinia enterocolitica superantigen. Human Immunology 43: 269–275.

Sundberg EJ, Deng L and Mariuzza RA (2007) TCR recognition of peptide/MHC class II complexes and superantigens. Seminars in Immunology 19: 262–271.

Sutkowski N, Conrad B, Thorley‐Lawson DA and Huber BT (2001) Epstein‐Barr virus transactivates the human endogenous retrovirus HERV‐K18 that encodes a superantigen. Immunity 15: 579–589.

Tai AK and Huber BT (2007) Viral superantigens in mice and humans. In: Kotb M and Fraser JD (eds) Superantigens: Molecular Basis for Their Role in Human Diseases, pp. 59–75. Washington, DC: ASM Press.

Tai AK, Luka J, Ablashi D and Huber BT (2009) HHV‐6A infection induces expression of HERV‐K18‐encoded superantigen. Journal of Clinical Virology 46: 47–48.

Tai AK, O'Reilly EJ, Alroy KA et al. (2008) Human endogenous retrovirus‐K18 Env as a risk factor in multiple sclerosis. Multiple Sclerosis 14: 1175–1180.

Todd J, Fishaut M, Kapral F and Welch T (1978) Toxic‐shock syndrome associated with phage‐group‐I Staphylococci. Lancet 2: 1116–1118.

Todd JK (2011) Toxic shock syndrome – evolution of an emerging disease. Advances in Experimental Medicine and Biology 697: 175–181.

Turcanova VL, Bundgaard B and Hollsberg P (2009) Human herpesvirus‐6B induces expression of the human endogenous retrovirus K18‐encoded superantigen. Journal of Clinical Virology 46: 15–19.

Wang N, Mattis DM, Sundberg EJ, Schlievert PM and Kranz DM (2010) A single, engineered protein therapeutic agent neutralizes exotoxins from both Staphylococcus aureus and Streptococcus pyogenes. Clinical and Vaccine Immunology 17: 1781–1789.

White J, Herman A, Pullen AM et al. (1989) The V beta‐specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell 56: 27–35.

Wucherpfennig KW (2001) Mechanisms for the induction of autoimmunity by infectious agents. Journal of Clinical Investigation 108: 1097–1104.

Yeung RSM (2004) The etiology of Kawasaki disease: a superantigen‐mediated process. Progress in Pediatric Cardiology 19: 115–122.

Further Reading

Kotb M and Fraser JD (eds) (2007) Superantigens: Molecular Basis and Role in Human Disease. ISBN 978‐1‐55581‐3. Washington, DC: ASM Press.

Krakauer T (ed.) (2002) Superantigen Protocols (Methods in Molecular Biology). ISBN: 0896039846. Totowa, NJ: Humana Press.

Marone G (ed.) (2007) Superantigens and Superallergens. ISBN 978–3–8055–8266–7. Basel: Karger.

Stow NW, Douglas R, Tantilipikorn P and Lacroix JS (2010) Superantigens. Otolaryngologic Clinics of North America 43(3): 489–502, vii.

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Langley, Ries J, and Renno, Toufic(Nov 2011) Superantigens. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001216.pub2]