CTLA-4 regulates allergen response by modulating GATA-3 protein level per cell.
T helper type 2 (Th2) cell differentiation requires the expression of GATA-3, a transcription factor that allows transcriptional activation of Th2 cytokine genes through chromatin remodelling. We investigated the role of the negative costimulatory receptor cytotoxic T-lymphocyte antigen 4 (CTLA-4) in the regulation of GATA-3 expression, Th2 differentiation and immunoglobulin production during the immune response to allergens. BALB/c mice were immunized with a recombinant major allergenic component of Parietaria judaica pollen, rPar j I, and treated with blocking anti-CTLA-4 or control antibodies. Results showed that in vivo CTLA-4 blockade enhanced the Par j I-specific immunoglobulin E (IgE) serum level. In contrast, Par j I-specific IgG2a serum level was reduced, suggesting that CTLA-4 blockade skewed immunoglobulin production towards interleukin-4 (IL-4) -dependent immunoglobulin isotypes. Consistently, CTLA-4 blockade increased the frequency of Par j I-specific Th2 cells but not Th1 cells, as well as IL-4 and IL-5 but not interferon-gamma production. Our data also showed that CTLA-4 blockade enhanced the GATA-3 : T-bet messenger RNA ratio. Interestingly, in vivo CTLA-4 blockade did not increase the frequency of GATA-3 protein-expressing cells. In contrast, it enhances GATA-3 protein level per cell. Further, in vitro results show that the anti-CTLA-4 monoclonal antibody, by competing with CD80 for CTLA-4 binding, induced an enhancement in the frequency of IL-4-producing cells that correlates with the increase in GATA-3 protein level per cell. In conclusion, CTLA-4, by affecting the level of GATA-3 per cell, contributes to keeping this factor under the threshold required to become a Th2 effector cell. Consequently, it affects IgE/IgG2a production and contributes to the outcome of allergen-specific immune responses.
Nasta
Francesca
F
ENEA, Unit of Biotechnology, Section of Toxicology and Biomedicine, Rome, Italy.
Corinti
Silvia
S
Bonura
Angela
A
Colombo
Paolo
P
Di Felice
Gabriella
G
Pioli
Claudio
C
D000485:Allergens / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D010940:Plant Proteins / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D000485:Allergens; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007074:Immunoglobulin G; C083860:Par j I protein, Parietaria judaica; D010940:Plant Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015847:Interleukin-4; D007073:Immunoglobulin E