Essential autocrine regulation by IL-21 in the generation of inflammatory T cells
Authors: Chen Dong
Stephanie S Watowich
Qiang Tian
Anton M Jetten
Li Ma
Gustavo Martinez
Xuexian O Yang
Roza Nurieva
Yongliang Zhang
Athanasia D Panopoulos
Kimberly Schluns
Journal: Nature (2007)
Discipline: Multidisciplinary
Keywords: CD4+ helper T cells; T(H) cells; effector subsets; cytokine expression; immunoregulatory function
Affiliations: Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA. 

Abstract:  After activation, CD4+ helper T (T(H)) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function. During this differentiation, T(H)1 and T(H)2 cells produce interferon-gamma and interleukin (IL)-4, respectively, as autocrine factors necessary for selective lineage commitment. A distinct T(H) subset, termed T(HIL-17), T(H)17 or inflammatory T(H) (T(H)i), has been recently identified as a distinct T(H) lineage mediating tissue inflammation. T(H)17 differentiation is initiated by transforming growth factor-beta and IL-6 (refs 5-7) and reinforced by IL-23 (ref. 8), in which signal transduction and activators of transcription (STAT)3 and retinoic acid receptor-related orphan receptor (ROR)-gamma mediate the lineage specification. T(H)17 cells produce IL-17, IL-17F and IL-22, all of which regulate inflammatory responses by tissue cells but have no importance in T(H)17 differentiation. Here we show that IL-21 is another cytokine highly expressed by mouse T(H)17 cells. IL-21 is induced by IL-6 in activated T cells, a process that is dependent on STAT3 but not ROR-gamma. IL-21 potently induces T(H)17 differentiation and suppresses Foxp3 expression, which requires STAT3 and ROR-gamma, which is encoded by Rorc. IL-21 deficiency impairs the generation of T(H)17 cells and results in protection against experimental autoimmune encephalomyelitis. IL-21 is therefore an autocrine cytokine that is sufficient and necessary for T(H)17 differentiation, and serves as a target for treating inflammatory diseases. 

Retracted: No

PubPeer comments:
 The authors in this paper proposed a **new notion** for decision making called u201c**complex picture fuzzy sets**.u201d In Definition 6, some set operations are defined for u201c**complex picture fuzzy sets**.u201d Let $$P_1=langle (y, 0e^{i0}, 1 e^{i0}, 0 e^{i0} )rangle$$ $$P_2=langle (y, 0e^{i0}, 0 e^{i0}, 1 e^{i0} )rangle$$ According to Definition 6, $$P1cap P_2 = langle (y, 0e^{i0}, 1 e^{i0}, 1 e^{i0} )rangle $$ Because $$0+1+1 1$$ it is clear that the result does not satisfy the requirement for a complex picture fuzzy set. **This means that the intersection of two complex picture fuzzy sets may not be a complex picture fuzzy set.** **Using the same example, it can be shown that the operations $P_1otimes P_2$ and $P_1wedge P_2$ defined in Definition 10 could return a result that is not a complex picture fuzzy number. Besides, the operations $lambda P_1$ and $P_1^{lambda}$ are also deficient for the same reason.** As a direct consequence, Theorem 2 is not valid because the proposed aggregation operation is based on the operations in Definition 10. Also, the decision making method presented in the rest of this paper is not sound.   ,