CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production.
T helper 2 (Th2) cells are critical to the induction of IgE antibody and allergic inflammation, but how the pathological pathways are controlled in nonallergic individuals remains unclear. Here we report that glycosylation-inhibiting factor (GIF) suppresses Th2 effector generation. GIF is a cytokine encoded by the same gene that codes for macrophage migration inhibitory factor (MIF). GIF-deficient mice demonstrated enhanced T-dependent antibody formation especially of IgE isotype and allergic airway inflammation with the generation of regulatory T cells unaffected. GIF-deficient macrophages and dendritic cells revealed normal responsiveness to toll-like receptor (TLR) ligands. GIF undergoes a unique posttranslational modification, cysteinylation. The modified GIF, mainly secreted by activated T cells derived from CD4(+)CD25(-) cells, inhibited IL-4 production by the same cells whereas the unmodified GIF showed no effect. Bone marrow chimera experiment demonstrated that T cell-derived GIF suppressed the generation of Th effectors that secrete IL-4. During the first 24 h of CD3/CD28 stimulation in vitro, GIF secreted from naïve CD4 cells acted on the same cells, maintained nuclear factor of activated T cells (NFAT)c2 in the nucleus, and repressed IL-4 mRNA levels. Thus, GIF represents a self-regulatory mechanism of Th2 cell generation from naïve CD4 cells, in which the posttranslational modification plays a crucial role.
Kim-Saijo
Misa
M
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Janssen
Edith M
EM
Sugie
Katsuji
K
D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006967:Hypersensitivity / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology; D008222:Lymphokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D050778:NFATC Transcription Factors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008222:Lymphokines; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D012333:RNA, Messenger; C013059:immunoglobulin-binding factors; D015847:Interleukin-4