title: A novel differentiation pathway from CD4⁺ T cells to CD4⁻ T cells for maintaining immune system homeostasis.
abstract: CD4(+) T lymphocytes are key players in the adaptive immune system and can differentiate into a variety of effector and regulatory T cells. Here, we provide evidence that a novel differentiation pathway of CD4(+) T cells shifts the balance from a destructive T-cell response to one that favors regulation in an immune-mediated liver injury model. Peripheral CD4(-)CD8(-)NK1.1(-) double-negative T cells (DNT) was increased following Concanavalin A administration in mice. Adoptive transfer of DNT led to significant protection from hepatocyte necrosis by direct inhibition on the activation of lymphocytes, a process that occurred primarily through the perforin-granzyme B route. These DNT converted from CD4(+) rather than CD8(+) T cells, a process primarily regulated by OX40. DNT migrated to the liver through the CXCR3-CXCL9/CXCL10 interaction. In conclusion, we elucidated a novel differentiation pathway from activated CD4(+) T cells to regulatory DNT cells for maintaining homeostasis of the immune system in vivo, and provided key evidence that utilizing this novel differentiation pathway has potential application in the prevention and treatment of autoimmune diseases.
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.|Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
authors.forename: G
authors.initials: G
authors.lastname: Sun
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
authors.forename: D
authors.initials: D
authors.lastname: Tian
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
authors.forename: K
authors.initials: K
authors.lastname: Liu
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.|Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China.|National Clinical Research Center for Digestive Diseases, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Cong
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.|National Clinical Research Center for Digestive Diseases, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.affiliation: Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.affiliation: Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.|Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China.|National Clinical Research Center for Digestive Diseases, Beijing, China.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D053804:Granzymes / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053278:OX40 Ligand / Q000172:deficiency / Q000235:genetics; D054353:Perforin / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D053278:OX40 Ligand; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D011993:Recombinant Fusion Proteins; D003208:Concanavalin A; D054353:Perforin; D053804:Granzymes; C000592415:perforin-granzyme B