T cells bearing invariant y5 T cell antigen receptors (TCR) localize to distinct epithelial sites in the adult mouse where they interact with non-classical antigen presenting cells such as epithelial cells. Many of these y8 T cell populations do not express traditional costimulatory molecules such as CD28 suggesting that they may rely on signals delivered through novel receptor-ligand interactions. We have identified AMIGA, a member of the junctional adhesion molecule family, as a costimulatory molecule for epithelial y8 T cells. AMIGA is expressed on all y5 T cells and in vitro mitogen activation leads to upregulated surface expression. Among lymphoid cells, AMIGA is preferentially expressed by y8 T cells although a small subpopulation of CD8+ ap T cells also express AMIGA after activation. Signals delivered through AMIGA costimulate skin and intestinal y5 T cell proliferation and cytokine release but not activation of any ap T cells or lymphoid y5 T cells. We will test the hypothesis that AMIGA expressed by epithelial y8 T cells binds to a ligand expressed on damaged epithelial cells and that interaction between this novel receptor-ligand pair delivers costimulatory signals to the y8T cell that are critical for participation in local immune responses including tissue homeostasis and repair. Together these studies should determine the roles of AMIGA in the activation and function of epithelial y8 T cells and may be applicable for manipulation of y8 T cell responses in epithelial disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064811-05
Application #
7727372
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Miller, Lara R
Project Start
2005-12-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$446,760
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Nielsen, Morten M; Witherden, Deborah A; Havran, Wendy L (2017) ?? T cells in homeostasis and host defence of epithelial barrier tissues. Nat Rev Immunol 17:733-745
Lee, Pedro; Gund, Rupali; Dutta, Abhik et al. (2017) Stimulation of hair follicle stem cell proliferation through an IL-1 dependent activation of ??T-cells. Elife 6:
Ramirez, Kevin; Witherden, Deborah A; Havran, Wendy L (2015) All hands on DE(T)C: Epithelial-resident ?? T cells respond to tissue injury. Cell Immunol 296:57-61
Nielsen, Morten M; Dyring-Andersen, Beatrice; Schmidt, Jonas D et al. (2015) NKG2D-dependent activation of dendritic epidermal T cells in contact hypersensitivity. J Invest Dermatol 135:1311-1319
Nielsen, Morten M; Lovato, Paola; MacLeod, Amanda S et al. (2014) IL-1?-dependent activation of dendritic epidermal T cells in contact hypersensitivity. J Immunol 192:2975-83
Witherden, Deborah A; Ramirez, Kevin; Havran, Wendy L (2014) Multiple Receptor-Ligand Interactions Direct Tissue-Resident ?? T Cell Activation. Front Immunol 5:602
Witherden, Deborah A; Havran, Wendy L (2013) Cross-talk between intraepithelial ?? T cells and epithelial cells. J Leukoc Biol 94:69-76
Komori, H Kiyomi; Witherden, Deborah A; Kelly, Ryan et al. (2012) Cutting edge: dendritic epidermal ýýýý T cell ligands are rapidly and locally expressed by keratinocytes following cutaneous wounding. J Immunol 188:2972-6
Macleod, Amanda S; Havran, Wendy L (2011) Functions of skin-resident ?? T cells. Cell Mol Life Sci 68:2399-408
Witherden, Deborah A; Havran, Wendy L (2011) Molecular aspects of epithelial ýýýý T cell regulation. Trends Immunol 32:265-71

Showing the most recent 10 out of 16 publications