Role of Mast Cells in Inflammation and Immunity

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DESCRIPTION (provided by applicant): The secretion of diverse mediators & cytokines by mast cells (MCs) activated by Fc-epsilon-RI-bound IgE & specific antigen (Ag) is widely regarded to be the main process by which MCs contribute significantly to allergic disorders such as atopic dermatitis & atopic asthma. However, there is strong evidence that effector T cells also have important roles in these disorders. In other settings, including cutaneous contact hypersensitivity (CHS), T cells clearly have critical roles but the contributions of the MC have been less certain, with different studies indicating that MCs can either enhance or have no effect on individual features of CHS responses. During the last period of support, we think that we have shed light on some of the factors which may importantly influence the roles of MCs in T cell-dependent host responses & diseases, including CHS. Our findings support the general hypothesis that: 1. Depending on the circumstances, MCs can importantly contribute to the development, magnitude and, remarkably, the resolution of several features of the pathology of T cell-dependent CHS responses; and 2. MCs can have these apparently paradoxical effects by exerting both direct & indirect actions on multiple recruited or resident cell types which participate in these reactions. Specifically, we found that, depending on the specific details of hapten sensitization & challenge, MCs can either markedly enhance or significantly limit the development, extent & duration of several features of the pathology associated with CHS in the mouse. We also reported evidence that: 1. the MC's ability to influence certain biological responses, including some which are relevant to CHS, may depend on occupancy of MC Fc-epsilon-RI by Ag-non-specific IgE; and 2. MCs can enhance the proliferation & cytokine production of multiple subsets of T cells in vitro, by mechanisms which either do or do not depend on IgE+Ag signaling via Fc-epsilon-RI, MC secretion of TNF, MC-T cell proximity or MC expression of co-stimulatory molecules (e.g., OX40L). Finally, we characterized in detail a new model for investigating MC function in vivo: c-kit mutant C57QUQ-Kit h/w/sh ("W sash") mice which have been selectively "repaired" of their MC deficiency by engraftment of in vitro-derived WT MCs or MCs with defined genetic abnormalities. We now wish to capitalize on these recent insights into the complex factors which can positively or negatively regulate MC functions during immune responses by pursuing the following aims: 1: Define the mechanisms by which MCs can modulate T cell proliferation & function; 2: Define the mechanisms by which MCs can enhance the elicitation phase & the pathological consequences of cutaneous CHS responses in vivo; & 3: Define the mechanisms by which MCs can limit the magnitude & duration of CHS responses. This work promises to improve our understanding of the complex potential roles of MCs, and IgE, in health & disease, as well as to improve our understanding of the pathology of CHS, a common occupational illness.