title: CD69 association with Jak3/Stat5 proteins regulates Th17 cell differentiation.
abstract: T-cell differentiation involves the early decision to commit to a particular pattern of response to an antigen. Here, we show that the leukocyte activation antigen CD69 limits differentiation into proinflammatory helper T cells (Th17 cells). Upon antigen stimulation in vitro, CD4(+) T cells from CD69-deficient mice generate an expansion of Th17 cells and the induction of greater mRNA expression of interleukin 17 (IL-17), IL 23 receptor (IL-23R), and the nuclear receptor retinoic acid-related orphan receptor γt (RORγt). In vivo studies with CD69-deficient mice bearing OTII T-cell receptors (TCRs) specific for OVA peptide showed a high proportion of antigen-specific Th17 subpopulation in the draining lymph nodes, as well as in CD69-deficient mice immunized with type II collagen. Biochemical analysis demonstrated that the CD69 cytoplasmic tail associates with the Jak3/Stat5 signaling pathway, which regulates the transcription of RORγt and, consequently, differentiation toward the Th17 lineage. Functional experiments in Th17 cultures demonstrated that the selective inhibition of Jak3 activation enhanced the transcription of RORγt. Moreover, the addition of exogenous IL-2 restored Stat5 phosphorylation and inhibited the enhanced Th17 differentiation in CD69-deficient cells. These results support the early activation receptor CD69 as an intrinsic modulator of the T-cell differentiation program that conditions immune inflammatory processes.
authors.affiliation: Department of Vascular Biology and Inflammation, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Martín
authors.forename: Manuel
authors.initials: M
authors.lastname: Gómez
authors.forename: Amalia
authors.initials: A
authors.lastname: Lamana
authors.forename: Arantxa
authors.initials: A
authors.lastname: Cruz-Adalia
authors.forename: Marta
authors.initials: M
authors.lastname: Ramírez-Huesca
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Ursa
authors.forename: María
authors.initials: M
authors.lastname: Yáñez-Mo
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D017931:DNA Primers / Q000235:genetics; D005260:Female; D066298:In Vitro Techniques; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000378:metabolism*; D037181:Lectins, C-Type / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017931:DNA Primers; D020381:Interleukin-17; D007376:Interleukin-2; D053616:Janus Kinase 3; D037181:Lectins, C-Type; D046912:Multiprotein Complexes; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010047:Ovalbumin; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D050799:STAT5 Transcription Factor; D000099192:CD69 Antigens; C528688:interleukin-23 receptor, mouse; C507935:Jak3 protein, mouse