title: T cell activation pathways: B7, LFA-3, and ICAM-1 shape unique T cell profiles.
abstract: Two signals are required for induction of cell proliferation and cytokine production in resting T cells. Occupancy of the T cell receptor by antigen/MHC complexes delivers the first signal to the T cell, while the second signal is provided by interaction with costimulatory ligands on APC. CD2, LFA-1, and CD28 are the major costimulatory and adhesive molecules on T cells and bind to the LFA-3, ICAM-1 and B7 ligands, respectively, on APC. LFA-3 plays a central role for naive and memory T helper cells during the early phase of an immune response. The LFA-3/CD2 pathway initiates strong antigen-independent cell adhesion, substantial expansion of naive T helper cells, and induction of large amounts of IFN-gamma in memory cells. The release of IFN-gamma may upregulate expression of ICAM-1 and B7 on APC and allows multiple adhesion pathways to amplify the immune response. The LFA-1/ICAM-1 pathway stimulates adhesion and cell proliferation more efficiently in memory T helper cells than in naive cells. Further, the results suggest that naive T helper cells express functionally inactive LFA-1 molecules on the cell surface, which may have a physiological role in keeping these cells in a resting state. B7 costimulation superinduces IL-2 production in both naive and memory T helper cells and generates long-lasting cell proliferation. This permits transition from an autocrine to a paracrine immune response. Coexpression of B7/LFA-3 provides an optimal APC function and enables a vigorous T cell response to minute amounts of antigen. AP-1 and NF-kappa B transcription factors are involved in the induction of several cytokine gene promoters and play a central role in the regulation of IL-2 gene transcription. LFA-3 costimulation only moderately enhances AP-1 DNA-binding activity and does not influence the NF-kappa B activity induced by TCR engagement, whereas B7 costimulation induces large amounts of NF-kappa B and AP-1 activity in T helper cells. The costimulatory ligands represent a family of adhesion molecules with considerable redundancy. Interfamily redundancy of LFA-3, B7, and ICAM ligands offers an opportunity to regulate distinct T cell response profiles in various microenvironments at separate time points of an immune response.
authors.affiliation: Department of Tumor Immunology, University of Lund, Sweden.
authors.forename: A G
authors.initials: AG
authors.lastname: Wingren
authors.forename: E
authors.initials: E
authors.lastname: Parra
authors.forename: M
authors.initials: M
authors.lastname: Varga
authors.forename: T
authors.initials: T
authors.lastname: Kalland
authors.forename: H O
authors.initials: HO
authors.lastname: Sjögren
authors.forename: G
authors.initials: G
authors.lastname: Hedlund
authors.forename: M
authors.initials: M
authors.lastname: Dohlsten
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology; D018968:CD58 Antigens / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D008213:Lymphocyte Activation; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D018968:CD58 Antigens; D018799:Intercellular Adhesion Molecule-1