title: Regulation of T-cell activation: differences among T-cell subsets.
abstract: Four regulatory phenomena appear to regulate differentially the activation of TH1, TH2, and CTL clones. First, IFN-gamma selectively inhibits proliferation of TH2 but not TH1 cells; lymphokine production by TH2 cells is not affected by IFN-gamma. In addition, when fresh OVA-specific HTL clones are derived in the presence of rIL-2 TH2 cells are preferentially obtained, whereas TH1 cells predominate if cloning is performed in rIL-2 plus rIFN-gamma. These results suggest that the presence of IFN-gamma during the course of an immune response would result in the preferential expansion of HTL of the TH1 phenotype. Proliferation of CTL clones is not influenced by IFN-gamma. Second, different APC populations appear to differentially activate TH1 and TH2 clones. Purified splenic B cells stimulate optimal proliferation of TH2 but not TH1 cells, whereas macrophage/dendritic cells appear to stimulate optimal proliferation of TH1 but not TH2 cells. Since both APC types stimulate lymphokine production by each of the HTL subsets, these results suggest the existence of TH1- and TH2-specific cofactors for growth. Third, high doses of immobilized anti-CD3 mAb inhibit IL-2-dependent proliferation of TH1 but not TH2 clones. Since this effect appears to require calcium, this observation suggests that TCR-mediated signalling events might differ between the two HTL subsets. Indeed, little or no increase in [Ca++]i can be detected in TH2 clones stimulated with Con-A, while such an increase is easily discernible in TH1 cells. Although high concentrations of immobilized anti-CD3 mAb inhibit IL-2-dependent proliferation of CTL clones, proliferation of these cells in response to immobilized anti-CD3 alone reaches a plateau. Since activation with anti-CD3 is thought to mimic antigenic stimulation, these results suggest that antigen concentration may play a role in determining which predominant T-cell types proliferate in a particular immunological situation. Fourth, pretreatment of TH1 cells, but not TH2 cells or CTL, with IL-2 results in decreased lymphokine production and proliferation in response to subsequent stimulation via the TCR. This antigen-responsive state appears to involve a defect in calcium-dependent signalling, providing additional evidence for different signalling mechanisms in TH1 and TH2 clones.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pathology, University of Chicago, IL 60637.
authors.forename: T F
authors.initials: TF
authors.lastname: Gajewski
authors.forename: S R
authors.initials: SR
authors.lastname: Schell
authors.forename: G
authors.initials: G
authors.lastname: Nau
authors.forename: F W
authors.initials: FW
authors.lastname: Fitch
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D008222:Lymphokines / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007376:Interleukin-2; D008222:Lymphokines; D011948:Receptors, Antigen, T-Cell; D003208:Concanavalin A; D007371:Interferon-gamma; D002118:Calcium