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International Immunology Advance Access originally published online on April 11, 2006
International Immunology 2006 18(5):637-644; doi:10.1093/intimm/dxh375
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Increased TGF-ß, Cbl-b and CTLA-4 levels and immunosuppression in association with chronic immune activation

Qibin Leng, Zvi Bentwich1 and Gadi Borkow2

R. Ben-Ari Institute of Clinical Immunology and AIDS Center, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot 76100, Israel
1 Present address: Department of Virology, Center for Infectious Diseases and AIDS, Ben Gurion University, Beer Sheba 84105, Israel
2 Present address: Cupron Inc. Hameyasdim 44, Gibton 76910, Israel

Correspondence to: G. Borkow; E-mail: gadi{at}cupron.com

In this study we investigated the mechanisms mediating T-cell hyporesponsiveness in chronically immune-activated individuals. We analyzed in healthy and persistently helminth-infected individuals the relationship between immune activation and general T-cell hyporesponsiveness, Th3/regulatory T-cell expression, transforming growth factor-ß (TGF-ß) secretion, CTL-associated antigen 4 (CTLA-4) levels, Casitas B-cell lymphoma-b (Cbl-b) (a negative regulator of T-cell activation) levels and phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinase (ERK)-1 and -2. We found a very significant increase in plasma levels of TGF-ß and intracellular pools of CTLA-4 and Cbl-b in association with immune activation, which correlates with decreased T-cell responses to anti-CD3 stimulation. We demonstrate that the impaired activity of ERK of peripheral T cells in highly immune-activated individuals is associated with increased levels of CTLA-4 and Cbl-b. Interestingly, in some, but not in all, of these immune-activated individuals, induction of Cbl-b intracellular pools occurs by TGF-ß or CTLA-4 stimulation. We suggest that the higher levels of CTLA-4 and TGF-ß, both involved in the induction of Cbl-b, point at potential mechanisms underlying general and antigen-specific immune hyporesponsiveness in chronically infected individuals.

Keywords: anergy, helminthic infections, hyporesponsiveness, signal transduction

Transmitting editor: S. Romagnani


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