Functional role for I kappa BNS in T cell cytokine regulation as revealed by targeted gene disruption.
Triggering of the TCR by cognate peptide/MHC ligands induces expression of I kappa BNS, a member of the I kappa B family of NF-kappaB inhibitors whose expression is associated with apoptosis of immature thymocytes. To understand the role of I kappa BNS in TCR triggering, we created a targeted disruption of the I kappa BNS gene. Surprisingly, mice lacking I kappa BNS show normal thymic progression but both thymocytes and T cells manifest reduced TCR-stimulated proliferation. Moreover, I kappa BNS knockout thymocytes and T cells produce significantly less IL-2 and IFN-gamma than wild-type cells. Transfection analysis demonstrates that I kappa BNS and c-Rel individually increase IL-2 promoter activity. The effect of I kappa BNS on the IL-2 promoter, unlike c-Rel, is dependent on the NF-kappaB rather than the CD28RE site; mutation of the NF-kappaB site extinguishes the induction of transcription by I kappa BNS in transfectants and prevents association of I kappa BNS with IL-2 promoter DNA. Microarray analyses confirm the reduction in IL-2 production and some IFN-gamma-linked transcripts in I kappa BNS knockout T cells. Collectively, our findings demonstrate that I kappa BNS regulates production of IL-2 and other cytokines induced via "strong" TCR ligation.
Touma
Maki
M
Laboratory of Immunobiology, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Antonini
Valeria
V
Kumar
Manoj
M
Osborn
Stephanie L
SL
Bobenchik
April M
AM
Keskin
Derin B
DB
Connolly
John E
JE
Grusby
Michael J
MJ
Reinherz
Ellis L
EL
Clayton
Linda K
LK
D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018390:Gene Targeting; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007519:Isoantigens / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D007519:Isoantigens; D008024:Ligands; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C454819:Nfkbid protein, mouse