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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI045888-01
Application #
2899406
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Plaut, Marshall
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
1999-09-30
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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
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; 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
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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