title: Role of IL-6, IL-1, and CD28 signaling in responses of mouse CD4+ T cells to immobilized anti-TCR monoclonal antibody.
abstract: Purified CD4+ T cells require TCR engagement and Ag-nonspecific co-stimulatory signals to produce IL-2 and proliferate. A number of recent studies have demonstrated that the interaction of the B7 molecule expressed on APC with the T cell-associated CD28 molecule provides a potent co-stimulatory signal to both freshly isolated CD4+ T cells and cloned Th1 cells. Earlier reports have described the role of cytokines, in particular IL-6 and IL-1, as costimulatory molecules for T cell activation. We previously reported that IL-6 and IL-1 synergize to co-stimulate proliferation of purified mouse CD4+ T cells in conjunction with anti-TCR mAb. In this report we explore the interaction of IL-6, IL-1, and CD28 signaling in the activation of mouse CD4+ T cells, and demonstrate that the co-stimulatory requirements of the cells vary depending on the mode of TCR stimulation. CD28 signaling is not sufficient to co-stimulate responses of high buoyant density CD4+ T cells to anti-TCR-conjugated agarose beads; there is an additional requirement that can be supplied by exogenous IL-6 but not by IL-1. In contrast, in responses to anti-TCR mAb that is passively bound to the bottom of culture wells, CD28 stimulation is sufficient to co-stimulate proliferation, resulting in a very high level of IL-2 production; there is no additional requirement for exogenous IL-6 or IL-1. Possible explanations for the differential requirement for IL-6 in the two systems are discussed. Our results are consistent with the notion that CD28 signaling plays a central role in co-stimulating T cell responses. However, the results also suggest that, depending on the nature of the TCR stimulus, T cell activation may also require additional co-stimulatory signals provided by cytokines.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley 94720.
authors.forename: M A
authors.initials: MA
authors.lastname: Holsti
authors.forename: J
authors.initials: J
authors.lastname: McArthur
authors.forename: J P
authors.initials: JP
authors.lastname: Allison
authors.forename: D H
authors.initials: DH
authors.lastname: Raulet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell