A Unique Costimulatory Pathway Defined with T Cell Hybridomas Specific for Myelin Basic Protein: Third Party Costimulators Restrict Antigenic Responses in Time and Space

Costimulatory signals regulate T cell responses to myelin basic protein (MBP) during induction of EAE in Lewis rats. However, the physiology of these costimulatory pathways has yet to be resolved. In this study, costimulatory pathways were defined by comparing MBP-stimulated IL-2 production by two types of T cell hybridoma (designated THYB-1 and THYB-2). THYB-1 hybrids required presentation of MBP/Ia complexes to stimulate IL-2 production, whereas THYB-2 hybrids also required the additional presence of costimulatory signals from radiosensitive (RS), nonadherent (NAdh) splenocytes (SPL). This study shows that allogeneic SPL, syngeneic B cells, or syngeneic T cells provided costimalatory signals to THYB-2 hybrids, although only syngeneic B cells were able to provide APC activity. Transduction of costimulatory signals did not occur across a microporous membrane but rather required close proximity of T cell hybrids with RS accessory cells. Simultaneous presence of costimulatory signals together with MHC-restricted antigen were required to initiate and maintain IL-2 production by THYB-2 hybrids. These findings support a model in which costimulatory molecules expressed by effector cells serve to restrict lymphokine production by T-helper cells. That is, THYB-2-like T-helper cells may mediate a paracrine pathway of IL-2 production that provides "help" to antigen-activated effector cell types that coexpress IL-2 receptors with appropriate costimulatory molecules.