The role of retinoic acid-related orphan receptor variant 2 and IL-17 in the development and function of human CD4+ T cells.
Th17 cells are defined by their capacity to produce IL-17, and are important mediators of inflammation and autoimmunity. Human Th17 cells express high levels of the retinoic acid-related orphan receptor variant 2 (RORC2), but it is currently unclear whether expression of this transcription factor alone is sufficient to recapitulate all the known properties of Th17 cells. We used lentivirus-mediated transduction to investigate the role of RORC2 in defining aspects of the human Th17 cell lineage. Expression of RORC2 induced production of IL-17A, IL-22, IL-6 and TNF-alpha, a Th17-cell-associated chemokine receptor profile and upregulation of CD161. RORC2-transduced T cells were hypo-responsive to TCR-mediated stimulation, a property shared with ex vivo Th17 cells and overcome by addition of exogenous IL-2 or IL-15. Co-culture experiments revealed that RORC2-expressing cells were partially resistant to Treg cells since production of IL-17 and proliferation were not suppressed. Evidence that IL-17 stimulates CD4(+) T cells to produce IL-2 and proliferate suggested that the resistance of Th17 cells to Treg-mediated suppression may be partly attributed to IL-17 itself. These findings demonstrate that expression of RORC2 in T cells has functional consequences beyond altering cytokine production and provides insight into the factors regulating the development of human Th17 cells.
Crome
Sarah Q
SQ
Department of Surgery, University of British Columbia and Immunity and Infection Research Centre, Vancouver Coastal Health Research Centre, Vancouver, Canada.
Wang
Adele Y
AY
Kang
Christine Y
CY
Levings
Megan K
MK
D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D005822:Genetic Vectors / Q000235:genetics; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D019707:Receptors, Chemokine / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014161:Transduction, Genetic
D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D020381:Interleukin-17; D055651:NK Cell Lectin-Like Receptor Subfamily B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D019707:Receptors, Chemokine; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D053804:Granzymes