title: Differential mTOR and ERK pathway utilization by effector CD4 T cells suggests combinatorial drug therapy of arthritis.
abstract: The signaling pathways utilized by naïve and experienced effector CD4 T cells during activation and proliferation were evaluated. While inhibition of either mTOR or MAPK alone was able to inhibit naïve T cell proliferation, both mTOR and MAPK (ERK) pathway inhibition was required to efficiently block experienced, effector CD4 T cell proliferation. This was demonstrated both in vitro, and in vivo by treating mice with collagen-induced arthritis using mTOR and/or ERK inhibitors. The combination of mTOR and ERK inhibition prevented or treated disease more efficiently than either agent alone. These data illustrate the different requirements of naïve and experienced effector CD4 T cells in the use of the mTOR and MAPK pathways in proliferation, and suggest that therapies targeting both the mTOR and MAPK pathways may be more effective than targeting either pathway alone in the treatment of CD4 T cell-mediated autoimmunity.
authors.affiliation: Stanford University School of Medicine, 269 Campus Drive West, Department of Medicine, Division of Immunology and Rheumatology, Stanford, CA 94305, USA.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Lin
authors.forename: Emily A
authors.initials: EA
authors.lastname: Stein
authors.forename: Michael T
authors.initials: MT
authors.lastname: Wong
authors.forename: Krishna J
authors.initials: KJ
authors.lastname: Kalpathy
authors.forename: Leon L
authors.initials: LL
authors.lastname: Su
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
authors.forename: C Garrison
authors.initials: CG
authors.lastname: Fathman
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D001549:Benzamides / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009005:Monosaccharides / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D001549:Benzamides; D001578:Benzopyrans; D002867:Chromones; D009005:Monosaccharides; D009025:Morpholines; C497449:SL0101; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C506614:mirdametinib; D004159:Diphenylamine; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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