The overall objective of this application is to determine the nature of ligands recognized by gamma/delta T-cells, and to ascertain the functional importance of gamma/delta T-cells responses to their ligand. Based on their previous findings and on others reported in the literature, we hypothesize that one groups of gamma/delta TCR ligands consists of soluble heterologous molecules that contain repetitive stimulatory patterns, or that aggregate to form such patterns, and which do not require presentation in order to be stimulatory. These ligands, which they have dubbed group 3 ligands, resemble and may include the type 2 T-cell-independent antigens of B-cells. They describe here two group 3 ligands that stimulate similar or identical subsets of gamma/delta T-cells: poly Glu50Tyr50 (pEY, historically termed """"""""poly-GT""""""""), a synthetic hetero-copolymeric peptide antigen; and cardiolipin (CL), a natural phospholipid present in prokaryotic and mitochondrial but not eukaryotic membranes. Although not a natural ligand, pEY, being a polypeptide, can easily be chemically modified and attached to other structures, and thus lends itself well to experiments designed to determine how group 3 antigens stimulate gamma/delta T-cells, and what is required for the stimulation. Thus, for mechanistic studies, they plan to focus on pEY as a model group 3 gamma/delta T-cell antigen, then return to CL, a natural ligand likely to be present during bacterial infection or inflammatory cell damage, to establish whether gamma/delta T-cell responses to group 3 antigens are important in immunobiology. Because of the probable overlap between group 3 gamma/delta T-cell ligands and B-cell type 2 T-cell-independent antigens, we anticipate that gamma/delta T-cells might in some circumstances be important in the development of antibody responses to certain immunogens.
The specific aims of this application are: 1. To define the mechanism by which pEY elicits responses of gamma/delta T-cells. 2. To characterize the response of normal gamma/delta T-cells to pEY and related antigens, and the ability of such cells to support antibody responses. 3. To test whether gamma/delta T-cells also respond to established type 2 T-cell-independent antigens, and whether they influence the reactivity of marginal zone B-cells to these antigens. 4. To establish the phospholipid cardiolipin as an antigen for innate gamma/delta T-cell responses, and to investigate the role of gamma/delta T-cells in the development of pathogenic anti-phospholipid antibodies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040611-06
Application #
6532729
Study Section
Immunobiology Study Section (IMB)
Program Officer
Kehn, Patricia J
Project Start
1997-07-01
Project End
2005-05-31
Budget Start
2002-08-01
Budget End
2003-05-31
Support Year
6
Fiscal Year
2002
Total Cost
$242,235
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Born, Willi K; Yin, Zhinan; Hahn, Youn-Soo et al. (2010) Analysis of gamma delta T cell functions in the mouse. J Immunol 184:4055-61
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Jin, Niyun; Roark, Christina L; Miyahara, Nobuaki et al. (2009) Allergic airway hyperresponsiveness-enhancing gammadelta T cells develop in normal untreated mice and fail to produce IL-4/13, unlike Th2 and NKT cells. J Immunol 182:2002-10
Huang, Yafei; Jin, Niyun; Roark, Christina L et al. (2009) The influence of IgE-enhancing and IgE-suppressive gammadelta T cells changes with exposure to inhaled ovalbumin. J Immunol 183:849-55
Hahn, Youn-Soo; Ji, Xu Yin; Woo, Sung-Il et al. (2008) Vgamma1+ gammadelta T cells reduce IL-10-producing CD4+CD25+ T cells in the lung of ovalbumin-sensitized and challenged mice. Immunol Lett 121:87-92
Cook, Laura; Miyahara, Nobuaki; Jin, Niyun et al. (2008) Evidence that CD8+ dendritic cells enable the development of gammadelta T cells that modulate airway hyperresponsiveness. J Immunol 181:309-19
Jin, Niyun; Miyahara, Nobuaki; Roark, Christina L et al. (2007) Airway hyperresponsiveness through synergy of gammadelta} T cells and NKT cells. J Immunol 179:2961-8
Born, Willi K; Jin, Niyun; Aydintug, M Kemal et al. (2007) gammadelta T lymphocytes-selectable cells within the innate system? J Clin Immunol 27:133-44
Simonian, Philip L; Roark, Christina L; Diaz del Valle, Fernando et al. (2006) Regulatory role of gammadelta T cells in the recruitment of CD4+ and CD8+ T cells to lung and subsequent pulmonary fibrosis. J Immunol 177:4436-43
Born, Willi K; Reardon, Christopher L; O'Brien, Rebecca L (2006) The function of gammadelta T cells in innate immunity. Curr Opin Immunol 18:31-8

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