IL-21 promotes Th17 differentiation, and Th17 cells that upregulate T-bet, IFN-γ, and GM-CSF drive experimental autoimmune diseases in mice. Anti-IL-21 treatment of autoimmune patients is therefore a therapeutic option, but the role of IL-21 in human T cell differentiation is incompletely understood. IL-21 was produced at high levels by human CD4+central memory T cells, suggesting that it is associated with early T cell differentiation. Consistently, it was inhibited by forced expression of T-bet or RORC2, the lineage-defining transcription factors of Th1 and Th17 effector cells, respectively. Although IL-21 was efficiently induced by IL-12 in naive CD4+T cells, it inhibited the generation of Th1 effector cells in a negative feedback loop. IL-21 was also induced by IL-6 and promoted Th17 differentiation, but it was not absolutely required. Importantly, however, IL-21 promoted IL- 10 secretion but inhibited IFN-γ and GM-CSF production in developing Th17 cells, and consequently prevented the generation of polyfunctional Th1/17 effector cells. Moreover, in Th17 memory cells, IL-21 selectively inhibited T-bet upregulation and GM-CSF production. In summary, IL-21 is a central memory T cell-associated cytokine that promotes Th17 differentiation and IL-10 production, but inhibits the generation of potentially pathogenic Th1/17 effector cells. These findings shed new light on the role of IL-21 in T cell differentiation, and have relevant implications for anti-IL-21 therapy of autoimmune diseases.
IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells / I. Kastirr, S. Maglie, M. Paroni, J.S. Alfen, G. Nizzoli, E. Sugliano, M. Crosti, M. Moro, B. Steckel, S. Steinfelder, K. Stölzel, C. Romagnani, F. Botti, F. Caprioli, M. Pagani, S. Abrignani, J. Geginat. - In: JOURNAL OF IMMUNOLOGY. - ISSN 0022-1767. - 193:7(2014), pp. 3322-3331.
|Titolo:||IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells|
|Settore Scientifico Disciplinare:||Settore MED/12 - Gastroenterologia|
|Data di pubblicazione:||2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.4049/jimmunol.1400775|
|Appare nelle tipologie:||01 - Articolo su periodico|