International Immunology Advance Access published online on April 11, 2006
International Immunology, doi:10.1093/intimm/dxh375
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1 R. Ben-Ari Institute of Clinical Immunology and AIDS Center, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot 76100, Israel
* To whom correspondence should be addressed. 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-
Received September 7, 2003
Accepted November 25, 2005
Article
Increased TGF-
Qibin Leng 1,
Zvi Bentwich 2,
and
Gadi Borkow 3 *
, Cbl-b and CTLA-4 levels and immunosuppression in association with chronic immune activation
2 R. Ben-Ari Institute of Clinical Immunology and AIDS Center, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot 76100, Israel; Present address: Department of Virology, Center for Infectious Diseases and AIDS, Ben Gurion University, Beer Sheba 84105, Israel
3 R. Ben-Ari Institute of Clinical Immunology and AIDS Center, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot 76100, Israel; Present address: Cupron Inc. Hameyasdim 44, Gibton 76910, Israel
Gadi Borkow, E-mail: gadi{at}cupron.com
Abstract 
(TGF-) 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- 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- or CTLA-4 stimulation. We suggest that the higher levels of CTLA-4 and TGF-, both involved in the induction of Cbl-b, point at potential mechanisms underlying general and antigen-specific immune hyporesponsiveness in chronically infected individuals.
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