Increased TGF-beta, Cbl-b and CTLA-4 levels and immunosuppression in association with chronic immune activation.
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-beta (TGF-beta) 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-beta 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-beta or CTLA-4 stimulation. We suggest that the higher levels of CTLA-4 and TGF-beta, both involved in the induction of Cbl-b, point at potential mechanisms underlying general and antigen-specific immune hyporesponsiveness in chronically infected individuals.
Leng
Qibin
Q
R. Ben-Ari Institute of Clinical Immunology and AIDS Center, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot 76100, Israel.
Bentwich
Zvi
Z
Borkow
Gadi
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D015153:Blotting, Western; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002908:Chronic Disease; D004789:Enzyme Activation; D005002:Ethiopia / Q000208:ethnology; D005260:Female; D006373:Helminthiasis / Q000097:blood / Q000276:immunology* / Q000469:parasitology; D006801:Humans; D007108:Immune Tolerance; D007557:Israel; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D050722:Oncogene Protein v-cbl / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D050722:Oncogene Protein v-cbl; D016212:Transforming Growth Factor beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3