TY - JOUR
T1 - Increased TGF-β, Cbl-b and CTLA-4 levels and immunosuppression in association with chronic immune activation
AU - Leng, Qibin
AU - Bentwich, Zvi
AU - Borkow, Gadi
N1 - Funding Information:
The work was supported by the Horowitz Foundation, granted to the Kaplan AIDS Center.
PY - 2006/5/15
Y1 - 2006/5/15
N2 - 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, T h 3/regulatory T-cell expression, transforming growth factor-β (TGF-β) 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-β 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-β or CTLA-4 stimulation. We suggest that the higher levels of CTLA-4 and TGF-β, both involved in the induction of Cbl-b, point at potential mechanisms underlying general and antigen-specific immune hyporesponsiveness in chronically infected individuals.
AB - 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, T h 3/regulatory T-cell expression, transforming growth factor-β (TGF-β) 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-β 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-β or CTLA-4 stimulation. We suggest that the higher levels of CTLA-4 and TGF-β, both involved in the induction of Cbl-b, point at potential mechanisms underlying general and antigen-specific immune hyporesponsiveness in chronically infected individuals.
KW - Anergy
KW - Helminthic infections
KW - Hyporesponsiveness
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=33646893933&partnerID=8YFLogxK
U2 - 10.1093/intimm/dxh375
DO - 10.1093/intimm/dxh375
M3 - Article
C2 - 16608902
AN - SCOPUS:33646893933
SN - 0953-8178
VL - 18
SP - 637
EP - 644
JO - International Immunology
JF - International Immunology
IS - 5
ER -