title: Regulatory T cells require TCR signaling for their suppressive function.
abstract: Regulatory T cells (Tregs) are a subset of CD4(+) T cells that maintain immune tolerance in part by their ability to inhibit the proliferation of conventional CD4(+) T cells (Tconvs). The role of the TCR and the downstream signaling pathways required for this suppressive function of Tregs are not fully understood. To yield insight into how TCR-mediated signals influence Treg suppressive function, we assessed the ability of Tregs with altered TCR-mediated signaling capacity to inhibit Tconv proliferation. Mature Tregs deficient in Src homology 2 domain containing leukocyte protein of 76 kDa (SLP-76), an adaptor protein that nucleates the proximal signaling complex downstream of the TCR, were unable to inhibit Tconv proliferation, suggesting that TCR signaling is required for Treg suppressive function. Moreover, Tregs with defective phospholipase C γ (PLCγ) activation due to a Y145F mutation of SLP-76 were also defective in their suppressive function. Conversely, enhancement of diacylglycerol-mediated signaling downstream of PLCγ by genetic ablation of a negative regulator of diacylglycerol kinase ζ increased the suppressive ability of Tregs. Because SLP-76 is also important for integrin activation and signaling, we tested the role of integrin activation in Treg-mediated suppression. Tregs lacking the adaptor proteins adhesion and degranulation promoting adapter protein or CT10 regulator of kinase/CT10 regulator of kinase-like, which are required for TCR-mediated integrin activation, inhibited Tconv proliferation to a similar extent as wild-type Tregs. Together, these data suggest that TCR-mediated PLCγ activation, but not integrin activation, is required for Tregs to inhibit Tconv proliferation.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Schmidt
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Wen
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Vishal J
authors.initials: VJ
authors.lastname: Sindhava
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; and.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; and.
authors.forename: Janis K
authors.initials: JK
authors.lastname: Burkhardt
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Enjun
authors.initials: E
authors.lastname: Yang
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Riese
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Maltzman
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Martha S
authors.initials: MS
authors.lastname: Jordan
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104; taku.kambayashi@uphs.upenn.edu.
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D004075:Diglycerides / Q000378:metabolism; D056747:Immunomodulation; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004075:Diglycerides; D016023:Integrins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins
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