학술논문
A two-amino-acid substitution in the transcription factor ROR[gamma]t disrupts its function in TH17 differentiation but not in thymocyte development
Document Type
Report
Author
Source
Nature Immunology. October 2017, Vol. 18 Issue 10, p1128, 11 p.
Subject
Language
English
ISSN
1529-2908
Abstract
Author(s): Zhiheng He [1]; Jian Ma [1]; Ruiqing Wang [1, 2]; Jing Zhang [1, 2]; Zhaofeng Huang [3]; Fei Wang [1]; Subha Sen [1]; Ellen V Rothenberg [4]; Zuoming Sun [...]
The transcription factor ROR[gamma]t regulates differentiation of the T[sub.H]17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of ROR[gamma]t prevents T[sub.H]17 cell-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in ROR[gamma]t (ROR[gamma]t[sup.M]) that 'preferentially' disrupted T[sub.H]17 differentiation but not thymocyte development. Mice expressing ROR[gamma]t[sup.M] were resistant to EAE associated with defective T[sub.H]17 differentiation but maintained normal thymocyte development and normal lymph-node genesis, except for Peyer's patches. ROR[gamma]t[sup.M] showed less ubiquitination at Lys69 that was selectively required for T[sub.H]17 differentiation but not T cell development. This study will inform the development of treatments that selectively target T[sub.H]17 cell-mediated autoimmunity but do not affect thymocyte development or induce lymphoma.
The transcription factor ROR[gamma]t regulates differentiation of the T[sub.H]17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of ROR[gamma]t prevents T[sub.H]17 cell-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in ROR[gamma]t (ROR[gamma]t[sup.M]) that 'preferentially' disrupted T[sub.H]17 differentiation but not thymocyte development. Mice expressing ROR[gamma]t[sup.M] were resistant to EAE associated with defective T[sub.H]17 differentiation but maintained normal thymocyte development and normal lymph-node genesis, except for Peyer's patches. ROR[gamma]t[sup.M] showed less ubiquitination at Lys69 that was selectively required for T[sub.H]17 differentiation but not T cell development. This study will inform the development of treatments that selectively target T[sub.H]17 cell-mediated autoimmunity but do not affect thymocyte development or induce lymphoma.