T cell activation and differentiation is dependent on TCR engagement of antigen and cooperating signals provided by several distinct receptor-ligand systems. The herpesvirus entry mediator (HVEM), a TNF superfamily member, engages LIGHT initiating costimulatory signals to T cells, yet HVEM also engages B and T lymphocyte attenuator (BTLA), an Ig superfamily member that provides an inhibitory signal to T cells. Substantial progress indicates that HVEM acts as a molecular switch between positive and inhibitory cosignaling in T cells. Moreover, the HVEM-BTLA system counter acts the closely related LTa(3-LT|3R system, which together regulates the homeostasis and expansion of specific subsets of dendritic cells in lymphoid organs. Thus understanding the regulatory mechanisms of this cytokine network should provide new insight into controlling immune responses. We found that LIGHT in either its membrane or soluble position modifies the binding of HVEM to BTLA, thus the mechanisms controlling the cellular compartmentalization of LIGHT may influence inhibitory signaling by BTLA. We propose to examine how various forms of LIGHT modulate the HVEM-BTLA interaction. Specifically how soluble ligands and polymorphic variants of LIGHT modify activation of BTLA. In addition, polymorphic variants of human LIGHT will be examined for their influence on LIGHT shedding and the enzyme involved in cleavage of membrane LIGHT will be identified using an expression cloning strategy. We will explore whether analogous pathways to HVEM-BTLA exist for other TNFR containing the conserved BTLA binding domain. HVEM-BTLA acts at a postmitotic step to limit dendritic cell expansion. The attenuation of death receptor signaling will be examined as one mechanism mediating the inhibitory affect of HVEM-BTLA on dendritic cell homeostasis using mouse and human models. These plans will provide a mechanistic understanding of how LTap and LIGHT signals are integrated to orchestrate intercellular communication between T lymphocytes and dendritic cells during immune responses. Lay summary: Our research identified an important set of molecules, termed cytokines, that control how immune cells communicate with each other. We demonstrated that altering the activity of these molecules changes the responses of cells. This research provides a new opportunity to modify the function of the immune system in autoimmune and infectious diseases
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