Regulation of IL-17 expression by the developmental pathway of CD4 T cells in the thymus.
CD4 T cells selected by MHC class II expressing thymocytes (T-CD4 T cells) have distinct effector functions compared to that of epithelial cell-selected CD4 T cells (E-CD4 T cells). T-CD4 T cells produce both Th1 and Th2 effector cytokines immediately after stimulation and also express IL-4 in addition to IFN-gamma under the Th1 differentiation condition. In the present study, we investigated the capability of T-CD4 T cells to become IL-17-producing cells. We found that T-CD4 T cells express reduced IL-17 under Th17-inducing conditions. T-CD4 T cells express very low levels of receptor for TGF-beta and IL-21 that are essential to induce IL-17 expression. In addition, the induction of RORgammat, a key transcription factor for IL-17 gene expression, was compromised in T-CD4 T cells under Th17 skewing conditions and ectopic expression of RORgammat restored IL-17 expression. The defect of IL-17 and RORgammat expression in T-CD4 T cells is cell intrinsic and not due to effects of a secreted factor. Thus, the developmental pathway of CD4 T cells in the thymus plays a critical role in controlling an immune response by suppressing the generation of the Th17 lineage.
Sofi
M Hanief
MH
Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, MI 48109-0620, USA.
Liu
Zhiping
Z
Zhu
Lingqiao
L
Yu
Qiao
Q
Kaplan
Mark H
MH
Chang
Cheong-Hee
CH
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002469:Cell Separation; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics* / Q000378:metabolism*; D015847:Interleukin-4 / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology*; D015534:Trans-Activators / Q000235:genetics
D020381:Interleukin-17; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D053655:Receptors, Interleukin-21; D018125:Receptors, Transforming Growth Factor beta; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4