Many cutaneous immune responses, such as melanoma and psoriasis, are mediated by CD8+ T cells. The factors restricting the development and effector function of CD8+ T cells specific for antigens in the skin remain largely un-investigated. Epi-cutaneous contact with haptens such as urushiol, the reactive agent in poison ivy, and subsequent challenge results in the development and elicitation of a T cell-mediated inflammatory response termed contact hypersensitivity (CHS). Recent results from the investigator's laboratory have indicated that epi-cutaneous application of mice with model haptens results in the induction of two populations of hapten-reactive T cells: 1) a CD8+ T cell population which produces IFN-g and mediates CHS; and 2) a CD4+ T cell population which produces IL-4 and IL-10 and regulates the magnitude and duration of CHS. On the basis of these results, the investigator hypothesizes that the effector function of CD8+ T cells mediating CHS is restricted: 1) during sensitization in skin draining lymph nodes by the functional phenotype of hapten-presenting Langerhans cells (LC) and the cytokine environment during T cell priming; and, 2) during the elicitation phase at the challenge site by the activity of regulatory CD4+ T cells. This hypothesis will be tested by performing experiments proposed in two specific aims.
In Specific Aim 1 the investigator will test the role of specific T cell-LC interactions, specifically CD28-B7 and CD40L-CD40, and cytokines, specifically IFN-g, IL-4 and IL-12, on the development and subsequent effector function of the CHS effector CD8+ T cells. The investigator will also test the mechanisms by which CD4+ T cells restrict the development of CD8+ T cells during hapten sensitization.
In Specific Aim 2, the investigator will elucidate the mechanisms by which CD8+ T cells mediate the CHS response by testing potential effector functions of the hapten-primed CD8+ T cells, including the production of pro-inflammatory cytokines and the ability to mediate cytolysis of hapten-presenting target cells. The investigator will also test mechanisms by which the regulatory CD4+ T cells restrict the magnitude and duration of the CD8+ T cell mediated response. The overall goal of these studies is to test and identify critical development factors which predestine the subsequent effector function of CD8+ T cells mediating responses to defined antigens in the skin and which limit the magnitude, duration and histopathology of the response. These studies will provide important new information regarding the mechanisms inducing effector CD8+ T cells in cutaneous immune responses and indicate the consequences of immune reactivity when protective regulatory mechanisms are altered.
