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ICOS deficiency


Primary antibody deficiency due to a genetic defect in the gene encoding the “inducible CoStimulator” (ICos)

Clinical background

ICOS deficiency presents as hypogammaglobulinemia (1). World wide 9 patients have been identified (2). Most patients present during early adulthood with increased rates of respiratory infections. Autoimmune phenomena and lymphoproliferative disorders have been described.

Immunologic background

The inducible Costimulator (ICOS, CD278) belongs to the CD28 family of costimulatory molecules and is exclusively expressed on T cells. Unlike the constitutive expression of CD28 ICOS is induced after (about 16 hours of) activation. ICOS shares most signalling pathways with CD28. While ICOS is less important for IL-2 production, IL10 as well as IL17 are clearly induced by ICOS co-stimulation. ICOS deficient patients exhibit severe reduction of class switched memory B cells suggesting a disturbed germinal center reaction (see also below).

Animal models

All ICOS-deficient mice (3-5) as well as ICOS-ligand deficient mice (6) confirm the important role of ICOS in the development of the germinal center reaction and class switched antibody response. While basal antibody levels were variable, most models show a reduction of at least some IgG subclasses. T cell development seems mostly unchanged. The initially observed TH2 shift was not confirmed by others and seems to be dependent on the condition and location of T cell stimulation. A preferential production of IL10 and IL17 was observed in different mice (7). CXCR5+ TFH development was also reduced in ICOS deficient mice (8, 9) as well as mice treated with soluble ICOS-L (10).


  1. Grimbacher,B., A.Hutloff, M.Schlesier, E.Glocker, K.Warnatz, R.Drager, H.Eibel, B.Fischer, A.A.Schaffer, H.W.Mages, R.A.Kroczek, and H.H.Peter. 2003. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat. Immunol. 4:261-268.
  2. Warnatz,K., L.Bossaller, U.Salzer, A.Skrabl-Baumgartner, W.Schwinger, B.M.van der, J.J.van Dongen, M.Orlowska-Volk, R.Knoth, A.Durandy, R.Draeger, M.Schlesier, H.H.Peter, and B.Grimbacher. 2006. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107:3045-3052.
  3. Dong,C., A.E.Juedes, U.A.Temann, S.Shresta, J.P.Allison, N.H.Ruddle, and R.A.Flavell. 2001. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409:97-101.
  4. McAdam,A.J., T.T.Chang, A.E.Lumelsky, E.A.Greenfield, V.A.Boussiotis, J.S.Duke-Cohan, T.Chernova, N.Malenkovich, C.Jabs, V.K.Kuchroo, V.Ling, M.Collins, A.H.Sharpe, and G.J.Freeman. 2000. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J. Immunol. 165:5035-5040.
  5. Tafuri,A., A.Shahinian, F.Bladt, S.K.Yoshinaga, M.Jordana, A.Wakeham, L.M.Boucher, D.Bouchard, V.S.Chan, G.Duncan, B.Odermatt, A.Ho, A.Itie, T.Horan, J.S.Whoriskey, T.Pawson, J.M.Penninger, P.S.Ohashi, and T.W.Mak. 2001. ICOS is essential for effective T-helper-cell responses. Nature 409:105-109.
  6. Mak,T.W., A.Shahinian, S.K.Yoshinaga, A.Wakeham, L.M.Boucher, M.Pintilie, G.Duncan, B.U.Gajewska, M.Gronski, U.Eriksson, B.Odermatt, A.Ho, D.Bouchard, J.S.Whorisky, M.Jordana, P.S.Ohashi, T.Pawson, F.Bladt, and A.Tafuri. 2003. Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses. Nat. Immunol. 4:765-772.
  7. Nurieva,R.I., P.Treuting, J.Duong, R.A.Flavell, and C.Dong. 2003. Inducible costimulator is essential for collagen-induced arthritis. J. Clin. Invest 111:701-706.
  8. Bossaller,L., J.Burger, R.Draeger, B.Grimbacher, R.Knoth, A.Plebani, A.Durandy, U.Baumann, M.Schlesier, A.A.Welcher, H.H.Peter, and K.Warnatz. 2006. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol. 177:4927-4932.
  9. Akiba,H., K.Takeda, Y.Kojima, Y.Usui, N.Harada, T.Yamazaki, J.Ma, K.Tezuka, H.Yagita, and K.Okumura. 2005. The Role of ICOS in the CXCR5+ Follicular B Helper T Cell Maintenance In Vivo. J Immunol. 175:2340-2348.
  10. Hu,Y.L., D.P.Metz, J.Chung, G.Siu, and M.Zhang. 2009. B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. J. Immunol. 182:1421-1428.

Responsible person

Dr. Klaus Warnatz


Last update: 2009-02-06 15:54:40
Immunologic phenotypes (ICOS deficiency)

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