T cell-intrinsic requirement for NF-kappa B induction in postdifferentiation IFN-gamma production and clonal expansion in a Th1 response.
NF-kappaB/Rel transcription factors are linked to innate immune responses and APC activation. Whether and how the induction of NF-kappaB signaling in normal CD4(+) T cells regulates effector function are not well-understood. The liberation of NF-kappaB dimers from inhibitors of kappaB (IkappaBs) constitutes a central checkpoint for physiologic regulation of most forms of NF-kappaB. To investigate the role of NF-kappaB induction in effector T cell responses, we targeted inhibition of the NF-kappaB/Rel pathway specifically to T cells. The Th1 response in vivo is dramatically weakened when T cells defective in their NF-kappaB induction (referred to as IkappaBalpha(DeltaN) transgenic cells) are activated by a normal APC population. Analyses in vivo, and IL-12-supplemented T cell cultures in vitro, reveal that the mechanism underlying this T cell-intrinsic requirement for NF-kappaB involves activation of the IFN-gamma gene in addition to clonal expansion efficiency. The role of NF-kappaB in IFN-gamma gene expression includes a modest decrease in Stat4 activation, T box expressed in T cell levels, and differentiation efficiency along with a more prominent postdifferentiation step. Further, induced expression of Bcl-3, a trans-activating IkappaB-like protein, is decreased in T cells as a consequence of NF-kappaB inhibition. Together, these findings indicate that NF-kappaB induction in T cells regulates efficient clonal expansion, Th1 differentiation, and IFN-gamma production by Th1 lymphocytes at a control point downstream from differentiation.
Corn
Radiah A
RA
Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Aronica
Mark A
MA
Zhang
Fuping
F
Tong
Yingkai
Y
Stanley
Sarah A
SA
Kim
Se Ryoung Agnes
SR
Stephenson
Linda
L
Enerson
Ben
B
McCarthy
Susan
S
Mora
Ana
A
Boothby
Mark
M
D019264:Adoptive Transfer; D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020825:T-Box Domain Proteins; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes / Q000276:immunology; D000098815:T-bet Transcription Factor
D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011518:Proto-Oncogene Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma