Many cutaneous immune responses, such as melanoma and psoriasis, are mediated by CD8+ T cells. The factors mediating recruitment of CD8+ T cells specific for antigens deposited in the skin remain unclear. Epicutaneous contact with haptens such as urushiol, the reactive agent in poison ivy, and subsequent challenge results in the development and elicitation of a CD8+ T cell-mediated inflammatory response termed contact hypersensitivity (CHS). Results from our laboratory have indicated that challenge of hapten-sensitized mice induces epidermal keratinocytes to produce the neutrophil chemoattractant Gro-alpha. This chemokine mediates neutrophil infiltration of the hapten challenge site and is required for the subsequent recruitment of the hapten-primed CD8+ effector T cells to the challenge site. On the basis of these results, we hypothesize that the antigen-specific T cell mediated immune response is elicited and regulated by cascades of chemokine production and cellular recruitment. This cascade is initiated by innate immune mechanisms which, in turn, mediate recruitment of the antigen- specific T cell component of the response. Following engagement of hapten, the CD8+ T cells produce IFN-gamma and this, in turn, stimulates stromal cells in the skin to produce potent chemoattractants (IP-10 and Mig) for antigen-primed T cells. These chemokines increase the inflammatory response by amlifying hapten-primed T cell infiltration into the challenge site. We further propose that hapten-specific T cells mediating down regulation of CHS inhibit chemokine production which recruits the innate and/or immune components to the hapten challenge site. Using histological, cellular immunology, an molecular approaches, this hypothesis will be tested by performing experiments proposed in three specific aims.
In Specific Aim 1 we will test the role of Gro-alpha mediated neutrophil recruitment as the first step in the elicitation of CHS.
In Specific Aim 2, we will test IP-10 and Mig as secondary chemokines required for the recruitment of CD4+ and CD8+ T cells during CHS.
In Specific Aim 3 we will test cytokine and molecular mechanisms which regulate chemokine production and leukocyte recruitment in CHS. The overall goal of these studies is to identify critical factors which regulate the recruitment 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.
Showing the most recent 10 out of 17 publications
