Many cutaneous immune responses, such as those in response to melanoma and psoriasis, are mediated by CD8+ T cells. The factors directing recruitment of CD8+ T cells specific for antigens deposited in the skin remain unclear. Epicutaneous contact with haptens or contact allergens such as urushiol, the reactive agent in poison ivy, and subsequent challenge results n the development and elicitation of a CD8+ T cell mediated inflammatory response termed contact hypersensitivity (CHS). Results from this laboratory during the initial funding cycle of this competitive renewal award indicated that challenge of hapten-sensitized mice induces epidermal keratinocytes to produce the neutrophil chemoattractants Gro-alpha/CXCL1 and MIP- 2/CXCL2. These chemokines direct neutrophil infiltration into the hapten challenge site and this infiltration is required for the subsequent recruitment of the hapten-primed CD8+ effector T cells into the challenge site to mediate the response. On the basis of these and our preliminary results we hypothesize that the antigen-specific T cell mediated response is elicited and regulated by neutrophil chemoattractant production and infiltration of neutrophils. This production is initiated by innate immune mechanisms which in turn mediate recruitment of the antigen-specific T cell component of the response. Following engagement of the hapten in the challenge site, the CD8+ T cells produce IFN-gamma and this in turn down-regulates neutrophil infiltration into the site and resolves the tissue inflammation. In addition, chemokine directed infiltration of neutrophils into skin tissue during sensitization with hapten regulates the function of epidermal dendritic cells that traffic to the skin draining lymph nodes and prime populations of hapten-specifc. Using histological, cellular immunology and molecular approaches, the proposed hypothesis will be tested by performing experiments in three specific aims.
In Specific Aim 1 we will test the production of Gro-alpha/CXCL1 and MIP-2/CXCL2 and the role of neutrophil recruitment during the elicitation of CHS.
Specific Aim 2 will test the role of IFN-gamma and IFN-gamma receptor signaling in down-regulating neutrophil infiltration during the elicitation of CHS response.
In Specific Aim 3 we will test the role of Gro-alpha/CXCL1 and MIP-2/CXCL2 mediated neutrophil recruitment during hapten sensitization on the function of hapten-presenting Langerhans cells and the development of hapten-specific T cells to distinct cytokine producing phenotypes. The overall goal of these studies is to identify critical factors that regulate the development and the function of antigen-primed CD8+ T cells to defined antigens deposited in the skin. Definition of these factors will expose new strategies to limit the magnitude, duration and histopathology of T cell mediated inflammation in the skin.
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