title: Differential targeting of IL-2 and T cell receptor signaling pathways selectively expands regulatory T cells while inhibiting conventional T cells.
abstract: Strategies to expand regulatory T cells hold therapeutic potential for ameliorating T cell-mediated autoimmunity. Recently, we reported that the requirements for T cell receptor signaling in conventional T cell and regulatory T cell proliferation are different. Using mutant mice that display defective T cell receptor-mediated phospholipase Cγ (PLCγ) activation, we hereby demonstrate that PLCγ activation is required for antigen-specific conventional T cell proliferation but not for IL-2-induced regulatory T cell proliferation. This led us to hypothesize that in conjunction with IL-2, pharmacological inhibition of T cell receptor-mediated PLCγ activation might offer a novel therapeutic strategy to expand regulatory T cells while simultaneously inhibiting conventional T cell proliferation. Indeed, using the calcineurin inhibitor Cyclosporine A to inhibit signaling downstream of PLCγ, we found that Cyclosporine A attenuated antigen-specific Tconv proliferation but permitted IL-2-induced regulatory T cell expansion in vitro and in vivo. Furthermore, the combination of Cyclosporine A and IL-2 was superior over either Cyclosporine A or IL-2 monotherapy in protection against the T cell-mediated demyelinating autoimmune disease mouse model, experimental autoimmune encephalomyelitis. Thus, a combination of TCR signaling inhibition and IL-2 might be a beneficial strategy in expanding regulatory T cells and inhibiting conventional T cell proliferation in autoimmune settings.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 10194, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satake
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Angela
authors.initials: A
authors.lastname: Archambault
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Leichner
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Wu
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D048708:Cell Growth Processes / Q000276:immunology; D016572:Cyclosporine / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D010738:Type C Phospholipases / Q000276:immunology
chemical_list: D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D016572:Cyclosporine; D010738:Type C Phospholipases
keywords: Autoimmunity; Conventional T cells; IL-2; Proliferation; Regulatory T cells; T cell receptor