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.
The serine/threonine kinase tumor progression locus 2 (Tpl2, also known as Map3k8/Cot) is a potent inflammatory mediator that drives the production of TNFα, IL-1β, and IFNγ. 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(-/-) naïve 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.
From the Departments of Infectious Diseases and.
Xin
X
Li
From the Departments of Infectious Diseases and.
Nicole V
NV
Acuff
From the Departments of Infectious Diseases and.
Angela R
AR
Peeks
From the Departments of Infectious Diseases and.
Rebecca
R
Kirkland
From the Departments of Infectious Diseases and.
Kara D
KD
Wyatt
Pathology, University of Georgia, Athens, Georgia 30602-7387.
Tamas
T
Nagy
From the Departments of Infectious Diseases and watfordw@uga.edu.
Wendy T
WT
Watford
D000818:Animals; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*
D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D011518:Proto-Oncogene Proteins; D016753:Interleukin-10; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse
Akt PKB; S6 kinase; T cell; cell differentiation; immunosuppression; mTOR complex (mTORC); serine/threonine protein kinase; tolerance