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.
|Kish, Danielle D; Gorbachev, Anton V; Fairchild, Robert L (2012) IL-1 receptor signaling is required at multiple stages of sensitization and elicitation of the contact hypersensitivity response. J Immunol 188:1761-71|
|Kish, Danielle D; Gorbachev, Anton V; Parameswaran, Neetha et al. (2012) Neutrophil expression of Fas ligand and perforin directs effector CD8 T cell infiltration into antigen-challenged skin. J Immunol 189:2191-202|
|Kish, Danielle D; Volokh, Nina; Baldwin 3rd, William M et al. (2011) Hapten application to the skin induces an inflammatory program directing hapten-primed effector CD8 T cell interaction with hapten-presenting endothelial cells. J Immunol 186:2117-26|
|Gorbachev, Anton V; Fairchild, Robert L (2010) CD4+CD25+ regulatory T cells utilize FasL as a mechanism to restrict DC priming functions in cutaneous immune responses. Eur J Immunol 40:2006-15|
|Kish, Danielle D; Li, Xiaoxia; Fairchild, Robert L (2009) CD8 T cells producing IL-17 and IFN-gamma initiate the innate immune response required for responses to antigen skin challenge. J Immunol 182:5949-59|
|Gorbachev, Anton V; Gasparian, Alexander V; Gurova, Katerina V et al. (2007) Quinacrine inhibits the epidermal dendritic cell migration initiating T cell-mediated skin inflammation. Eur J Immunol 37:2257-67|
|Gorbachev, Anton V; Kobayashi, Hirohito; Kudo, Daisuke et al. (2007) CXC chemokine ligand 9/monokine induced by IFN-gamma production by tumor cells is critical for T cell-mediated suppression of cutaneous tumors. J Immunol 178:2278-86|
|Kish, Danielle D; Gorbachev, Anton V; Fairchild, Robert L (2007) Regulatory function of CD4+CD25+ T cells from Class II MHC-deficient mice in contact hypersensitivity responses. J Leukoc Biol 82:85-92|
|Gorbachev, Anton V; Fairchild, Robert L (2006) Activated NKT cells increase dendritic cell migration and enhance CD8+ T cell responses in the skin. Eur J Immunol 36:2494-503|
|Kish, Danielle D; Gorbachev, Anton V; Fairchild, Robert L (2005) CD8+ T cells produce IL-2, which is required for CD(4+)CD25+ T cell regulation of effector CD8+ T cell development for contact hypersensitivity responses. J Leukoc Biol 78:725-35|
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