The B7:CD28 receptor family members provide activating or inhibitory signals that are critical regulators of the inflammatory process and T cell function in vitro and in vivo. These receptors exert there influence throughout the inflammatory response, regulating the initiation, effector and resolution phases of allergic airway inflammation. CD28 is required for allergic airway inflammation in a murine model of asthma. Interestingly, the resolution of inflammation is also an active process that depends upon signaling through inhibitory receptors of the B7:CD28 family. Thus, in vivo, continued inflammation or resolution is determined by the balance of activating versus inhibitory signals delivered through receptors of the B7:CD28 family. While headway has been made in understanding the mechanism of CD28 and related proteins, significant questions remain as to how these signals are integrated to yield specific immune responses. Our studies have determined that CD28 regulates both the initiation of T cell activation, as well as the maintenance of effector function. We have identified distinct signaling motifs in the cytoplasmic tail of CD28 that selectively regulate T cell proliferation, cytokine secretion and survival in vitro. We hypothesize that these domains, termed the proximal and distal CD28 signaling motifs, regulate the initiation and maintenance of effector function in vivo. We have generated knock in mice expressing specific point mutations in the proximal and distal CD28 signaling motifs. These are a novel and potent tool to dissect how the cellular and biochemical consequences of CD28 ligation are integrated in vitro and in vivo.
In Specific Aim 1 we will utilize these to determine how signals from the proximal and distal CD28 signaling motifs regulate allergic airway inflammation. To determine how CD28 signaling is counterbalanced, we have obtained mice deficient in the newly described B and T Lymphocyte attenuator (BTLA), an inhibitory receptor of the CD28 family. Our Preliminary Data demonstrates that BTLA is important in limiting lung inflammation. We hypothesize that the expression of BTLA on activated T cells is engaged by ligands on cells in the lung, and that this signal terminates the inflammatory response.
In Specific Aim 2 we will test this and determine the mechanism by which BTLA limits inflammation. Characterization of the balance between activating and inhibitory signals from the B7:CD28 receptor family members will provide the framework to develop strategies to manipulate either activating or inhibitory signals to favorably alter the initiation, effector, and resolution phases of allergic inflammation. ? ?
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