Regulation of Th2 cytokine expression in NKT cells: unconventional use of Stat6, GATA-3, and NFAT2.
NKT cells are unique in that they can produce high levels of both Th1 and Th2 cytokines, yet little is known about how NKT cells control the transcription of Th2 cytokines. The expression of IL-4 by NKT cells is independent of the Th2-associated transcription factor Stat6. We have found that Stat6 is critical for the expression of IL-5, IL-10, and IL-13 by NKT cells. However, the Th2 cell-associated transcription factor GATA-3, normally induced by Stat6 activation, is expressed at low levels in NKT cells. CD4+ NKT cells are highly enriched for Th2 cytokine expression compared with CD4- NKT cells, and we searched for transcription factors that are up-regulated in CD4+ NKT cells that could control Th2 cytokine expression. We found that the NFAT family member NFAT2 is selectively increased in CD4+ NKT cells. We tested the roles of NFAT2 and also GATA-3 in Th2 cytokine expression by retrovirus-mediated gene transduction into NKT cells and nonpolarized conventional T cells. Expression of NFAT2 increased the expression of IL-4 in both NKT cells and conventional T cells, and NFAT2 activated IL-10 in conventional T cells but not in NKT cells. GATA-3 strongly activated IL-4, IL-5, and IL-13 expression in conventional T cells but had comparatively weak effects on these cytokines in NKT cells. Thus, NFAT2, GATA-3, and Stat6 have surprisingly different roles in NKT cells than in conventional T cells. We propose that one mechanism by which CD4+ NKT cells express IL-4 independent of Stat6 is via increased NFAT2 activity.
Wang
Zheng-Yu
ZY
Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Kusam
Saritha
S
Munugalavadla
Veerendra
V
Kapur
Reuben
R
Brutkiewicz
Randy R
RR
Dent
Alexander L
AL
D000818:Animals; D001483:Base Sequence; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D007694:Killer Cells, Natural / Q000145:classification / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic
D016207:Cytokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D016572:Cyclosporine