It is now widely accepted that recognition of peptide/MHC complexes on antigen presenting cells (APCs) is not sufficient for most aspects of CD4 T-cell function, and that additional interactions between T-cell co-receptors and APC accessory molecules are required for optimal cell growth, cytokine secretion, and induction of effector function. The majority of studies of costimulation have focused on the interactions between CD28 and B7, and CD40L and CD40, leading to the current concept that these are the critical molecules involved in T-cell responses. However, work by the investigator has shown that other receptor/ligand pairs can function as costimulators, for example LFA-1/ICAM-1. The goal of the current application is evaluation of the possibility that the Ox-40/Ox-40L and 4-1BB/4-1BBL interactions, which are expressed on T-cells and APC after activation, transduce critical costimulatory signals late in the response. In vitro experiments will explore the expression of Ox-40 and 4-1BB on naive, effector, and memory T-cells derived from TCR transgenic mice following stimulation with L cells expressing Ox-40L, 4-1BBL, B7, and/or ICAM-1, or physiological APC such as B-cells or dendritic cells. T-cell proliferation, Th1 and Th2 lymphokine production, and rescue from apoptosis will be measured. The role of the Ox-40/Ox-40L and 4-1BB/4-1BBL interactions in vivo in primary and secondary responses will be tested in normal mice and adoptive transfer recipients. Finally, the role of Ox-40/Ox-40L and 4-1BB/4-1BBL interactions in collagen-induced arthritis will be tested.
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