title: Selective targeting of transforming growth factor-beta1 into TCR/CD28 signalling plasma membrane domains silences T cell activation.
abstract: TGFβ1 (Transforming Growth Factor-beta1) is a versatile regulator of T cell immune responses. Depending on its context in the immunological environment, TGFβ1 guides T cells toward specific activation programs including TH17 and regulatory T cell activities. Moreover, TGFβ signals function in immune homeostasis by directly attenuating T cell effector activities. We uncovered a novel context under which TGFβ1 stringently and reversibly silences activation responses of resting human T cells to TCR/CD28 stimulating surfaces:Using ligand-presenting beads, TGFβ1 and TCR/CD28-activating signals were directed into defined plasma membrane domains of T cells. Selective targeting of TGFβ1 cytokine into TCR/CD28 signalling plasma membrane domains held back early response of TCR-proximal tyrosine phosphorylation and bead engulfment at activation sites. Consequently, downstream induction of proliferation and cytokine secretion were stringently attenuated. After extended incubation with TGFβ1-presenting beads, silenced T cells became receptive again to activation by renewed TCR/CD28-stimuli, indicating that the unresponsive state of T cells was reverted and did not reflect long-lasting anergy or decrease in T cell viability. These findings outline a new strategy of physically linking TGFβ1 and TCR-activating functions for the treatment of disease and pathological conditions which are caused by unwanted T cell activity.
authors.affiliation: Institute for Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Leipziger Straße 44, Magdeburg, D 39120, Germany. tharder@faciendum.org.
authors.forename: Thomas
authors.initials: T
authors.lastname: Harder
authors.forename: Karina
authors.initials: K
authors.lastname: Guttek
authors.forename: Lars
authors.initials: L
authors.lastname: Philipsen
authors.forename: Luca
authors.initials: L
authors.lastname: Simeoni
authors.forename: Burkhart
authors.initials: B
authors.lastname: Schraven
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
mesh_terms: D018106:CD28 Antigens / Q000378:metabolism*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D053773:Transforming Growth Factor beta1