Mast cells' contribution to T cell immunity

Northwestern University At Chicago, Evanston IL

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Abstract

Mast cells have a well-established role in the inflammatory processes that regulate allergic responses. Recent data have implicated mast cells in a variety of other pathologic and protective immune responses. These include exacerbation of symptoms in murine models of multiple sclerosis (Experimental allergic encephalomyelitis - EAE) and arthritis and resistance to bacterial infections. In addition to mediators that are known to affect the recruitment and activation state of cells of the innate immune system, mast cells also express many molecules that have documented effects on the regulation of adaptive immune responses. These include CD40L, IL-2, IL-4, IL-7, IL-15, IL-23, LTB4 and histamine. We recently compared the T cell responses of mast cell-deficient mice (W/Wv) with their wild type littermates after immunization with a myelin peptide in CFA, a protocol used to induce EAE. Although there is no inherent deficit in W/Wv-derived T cells activated in a mast cell-sufficient environment, several indices of activation including stimulation-dependent changes in the expression of CD44, CD11a, CD69 and CD62L are attenuated in T cells primed in a mast cell-deficient setting as is the ability to express IFN gamma. Notably, both the CD4+ and CD8+ T cell responses were consistently and significantly affected. The sub-optimal CDS response may be due to inefficient mast cell-dependent T cell help. Alternatively, it may reflect the more direct influence of mast cells on CD8+ T cells. Using a well-defined Listeria monocytogenes infection model, experiments in this application will test the hypothesis that mast cells contribute to a microenvironment that shapes several events governing CD4+ and CD8+ T cell function. The specific aims are as follows: 1. To determine the effect of mast cell-deficiency on CD4+ and CD8+ T responses after infection with a recombinant L. monocytogenes expressing gp33-41, the class I LCMV epitope (rLM33). 2. To examine the influence of mast cells on dendritic cell maturation, migration and T cell stimulatory function in rl_M33 infected mice. 3. 3. To assess the changes in mast cell phenotype during rLM33 infection and determine their relationship to alterations in T cell responses