T-CELL ACTIVATION PATHWAYS - B7, LFA-3, AND ICAM-1 SHAPE UNIQUE T-CELL PROFILES

Two signals are required for induction of cell proliferation and cytok ine 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 ligand s on APC. CD2, LFA-1, and CD28 are the major costimulatory and adhesiv e molecules on T cells and bind to the LFA-3, ICAM-1 and B7 ligands, r espectively, 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, substa ntial expansion of naive T helper cells, and induction of large amount s of IFN-gamma in memory cells. The release of IFN-gamma may upregulat e expression of ICAM-1 and B7 on APC and allows multiple adhesion path ways to amplify the immune response. The LFA-1/ICAM-1 pathway stimulat es 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 i n a resting state. B7 costimulation superinduces IL-2 production in bo th naive and memory T helper cells and generates long-lasting cell pro liferation. This permits transition from an autocrine to a paracrine i mmune response. Coexpression of B7/LFA-3 provides an optimal APC funct ion and enables a vigorous T cell response to minute amounts of antige n. AP-1 and NF-kappa B transcription factors are involved in the induc tion of several cytokine gene promoters and play a central role in the regulation of IL-2 gene transcription, LFA-3 costimulation only moder ately 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 cell s. 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 respon se profiles in various microenvironments at separate time points of an immune response.