PMID- 27261457 OWN - NLM STAT- MEDLINE DCOM- 20170504 LR - 20211204 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 291 IP - 32 DP - 2016 Aug 5 TI - Tumor Progression Locus 2 (Tpl2) Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Inhibits Forkhead Box P3 (FoxP3) Expression, and Limits Regulatory T Cell (Treg) Immunosuppressive Functions. PG - 16802-15 LID - 10.1074/jbc.M116.718783 [doi] AB - The serine/threonine kinase tumor progression locus 2 (Tpl2, also known as Map3k8/Cot) is a potent inflammatory mediator that drives the production of TNFalpha, IL-1beta, and IFNgamma. We previously demonstrated that Tpl2 regulates T cell receptor (TCR) signaling and modulates T helper cell differentiation. However, very little is known about how Tpl2 modulates the development of regulatory T cells (Tregs). Tregs are a specialized subset of T cells that express FoxP3 and possess immunosuppressive properties to limit excess inflammation. Because of the documented role of Tpl2 in promoting inflammation, we hypothesized that Tpl2 antagonizes Treg development and immunosuppressive function. Here we demonstrate that Tpl2 constrains the development of inducible Tregs. Tpl2(-/-) naive CD4(+) T cells preferentially develop into FoxP3(+) inducible Tregs in vitro as well as in vivo in a murine model of ovalbumin (OVA)-induced systemic tolerance. Treg biasing of Tpl2(-/-) T cells depended on TCR signal strength and corresponded with reduced activation of the mammalian target of rapamycin (mTOR) pathway. Importantly, Tpl2(-/-) Tregs have basally increased expression of FoxP3 and immunosuppressive molecules, IL-10 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Furthermore, they were more immunosuppressive in vivo in a T cell transfer model of colitis, as evidenced by reduced effector T cell accumulation, systemic production of inflammatory cytokines, and colonic inflammation. These results demonstrate that Tpl2 promotes inflammation in part by constraining FoxP3 expression and Treg immunosuppressive functions. Overall, these findings suggest that Tpl2 inhibition could be used to preferentially drive Treg induction and thereby limit inflammation in a variety of autoimmune diseases. CI - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Li, Xin AU - Li X AD - From the Departments of Infectious Diseases and. FAU - Acuff, Nicole V AU - Acuff NV AD - From the Departments of Infectious Diseases and. FAU - Peeks, Angela R AU - Peeks AR AD - From the Departments of Infectious Diseases and. FAU - Kirkland, Rebecca AU - Kirkland R AD - From the Departments of Infectious Diseases and. FAU - Wyatt, Kara D AU - Wyatt KD AD - From the Departments of Infectious Diseases and. FAU - Nagy, Tamas AU - Nagy T AD - Pathology, University of Georgia, Athens, Georgia 30602-7387. FAU - Watford, Wendy T AU - Watford WT AD - From the Departments of Infectious Diseases and watfordw@uga.edu. LA - eng GR - R01 AI099058/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20160603 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (CTLA-4 Antigen) RN - 0 (Ctla4 protein, mouse) RN - 0 (Forkhead Transcription Factors) RN - 0 (Foxp3 protein, mouse) RN - 0 (IL10 protein, mouse) RN - 0 (Proto-Oncogene Proteins) RN - 130068-27-8 (Interleukin-10) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) RN - EC 2.7.11.25 (Map3k8 protein, mouse) SB - IM MH - Animals MH - CTLA-4 Antigen/genetics/immunology MH - Cell Differentiation/genetics/*immunology MH - Colitis/genetics/immunology/pathology/therapy MH - Disease Models, Animal MH - Forkhead Transcription Factors/genetics/*immunology MH - Gene Expression Regulation/*immunology MH - *Immune Tolerance MH - Interleukin-10/genetics/immunology MH - MAP Kinase Kinase Kinases/genetics/*immunology MH - Mice MH - Mice, Knockout MH - Proto-Oncogene Proteins/genetics/*immunology MH - T-Lymphocytes, Regulatory/*immunology/pathology MH - TOR Serine-Threonine Kinases/genetics/*immunology PMC - PMC4974392 OTO - NOTNLM OT - Akt PKB OT - S6 kinase OT - T cell OT - cell differentiation OT - immunosuppression OT - mTOR complex (mTORC) OT - serine/threonine protein kinase OT - tolerance EDAT- 2016/06/05 06:00 MHDA- 2017/05/05 06:00 PMCR- 2017/08/05 CRDT- 2016/06/05 06:00 PHST- 2016/01/29 00:00 [received] PHST- 2016/06/05 06:00 [entrez] PHST- 2016/06/05 06:00 [pubmed] PHST- 2017/05/05 06:00 [medline] PHST- 2017/08/05 00:00 [pmc-release] AID - S0021-9258(20)35400-4 [pii] AID - M116.718783 [pii] AID - 10.1074/jbc.M116.718783 [doi] PST - ppublish SO - J Biol Chem. 2016 Aug 5;291(32):16802-15. doi: 10.1074/jbc.M116.718783. Epub 2016 Jun 3.