CTLA-4 regulates the requirement for cytokine-induced signals in T(H)2 lineage commitment.
The relative importance of the cytokine milieu versus cytolytic T lymphocyte-associated antigen 4 (CTLA-4) and T cell receptor signal strength on T cell differentiation remains unclear. Here we have generated mice deficient for signal transducer and activator of transcription 6 (STAT6) and CTLA-4 to determine the role of CTLA-4 in cytokine-driven T cell differentiation. CTLA-4-deficient T cells bypass the need for STAT6 in the differentiation of T helper type 2 (T(H)2) cells. T(H)2 differentiation of cells deficient for both STAT6 and CTLA-4 is accompanied by induction of GATA-3 and the migration of T(H)2 cells to peripheral tissues. CTLA-4 deficiency also affects the balance of the nuclear factors NFATc1 and NFATc2, and enhances activation of NF-kappaB. These results suggest that CTLA-4 has a critical role in T cell differentiation and that STAT6-dependent T(H)2 lineage commitment and stabilization can be bypassed by increasing the strength of signaling through the T cell receptor.
Bour-Jordan
Hélène
H
UCSF Diabetes Center and Department of Medicine, University of California San Francisco, 94143, USA.
Grogan
Jane L
JL
Tang
Qizhi
Q
Auger
Julie A
JA
Locksley
Richard M
RM
Bluestone
Jeffrey A
JA
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002454:Cell Differentiation; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D050990:GATA3 Transcription Factor; D018796:Immunoconjugates; D017578:Immunoglobulin Class Switching; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D018796:Immunoconjugates; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C494007:Nfatc2 protein, mouse; D009687:Nuclear Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000069594:Abatacept