T-bet down-modulation in tolerized Th1 effector CD4 cells confers a TCR-distal signaling defect that selectively impairs IFN-gamma expression.
When Th1 effector CD4 cells encounter tolerizing Ag in vivo, their capacity to express the effector cytokines IFN-gamma and TNF-alpha is lost more rapidly than noneffector functions such as IL-2 production and proliferation. To localize the relevant intracellular signaling defects, cytokine expression was compared following restimulation with Ag vs agents that bypass TCR-proximal signaling. IFN-gamma and TNF-alpha expression were both partially rescued when TCR-proximal signaling was bypassed, indicating that both TCR-proximal and -distal signaling defects impair the expression of these two effector cytokines. In contrast, bypassing TCR-proximal signaling fully rescued IL-2 expression. T-bet, a transcription and chromatin remodeling factor that is required to direct the differentiation of naive CD4 cells into IFN-gamma-expressing Th1 effectors, was partially down-modulated in tolerized Th1 effectors. Enforcing T-bet expression during tolerization selectively rescued the ability to express IFN-gamma, but not TNF-alpha. Conversely, expression of a dominant-negative T-bet in Th1 effectors selectively impaired the ability to express IFN-gamma, but not TNF-alpha. Analysis of histone acetylation at the IFN-gamma promoter further suggested that down-modulation of T-bet expression during Th1 effector CD4 cell tolerization does not impair IFN-gamma expression potential through alterations in chromatin structure.
Long
Meixiao
M
Center for Immunotherapy of Cancer and Infectious Diseases and Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Slaiby
Aaron M
AM
Hagymasi
Adam T
AT
Mihalyo
Marianne A
MA
Lichtler
Alexander C
AC
Reiner
Steven L
SL
Adler
Adam J
AJ
D019264:Adoptive Transfer; D000818:Animals; D001483:Base Sequence; D042002:Chromatin Assembly and Disassembly; D004247:DNA / Q000235:genetics; D015536:Down-Regulation; D015870:Gene Expression; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000098815:T-bet Transcription Factor
D007376:Interleukin-2; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D004247:DNA