A salient feature of the immune system is the remarkable heterogeneity of T lymphocytes and the functional diversity represented by the collection of specialized cellular subsets. T lymphocyte subpopulations can be classified according to the differential expression of T cell receptors, surface markers, adhesion molecules, cytokines and their receptors. A thorough understanding of the phenotype, function and activation requirements of individual T cell subsets is crucial to an understanding of autoimmune disease and the mechanisms of immunity to infection. A newly recognized subdivision of T cells is based on the differential expression of T cell receptors. The T cell receptor (TCR) is a disulfide bond-linked heterodimer composed of an alpha (alpha)- chain paired with a beta (beta)-chain or a gamma (gamma)-chain associated with a delta (delta)-chain. Very early in T cell development, cells become committed to express either alpha and beta chain gene products or gamma and delta proteins. As such, distinct T cell lineages are generated that express either the alpha/beta TCR or the gamma/delta TCR. While T lymphocytes that express the T cell receptor represent a small subset of T cells present in lymphoid organs, gamma/delta T cells appear to predominate in epithelial tissue. This tissue localization may indicate their involvement in """"""""front line"""""""" defense mechanisms by recognition of microbial products or induced self antigens present at these sites. The peritoneal cavity of mice is also a site for preferential expression and induction of gamma/delta T cells. Intraperitoneal injection of pathogenic bacteria or their toxins results in a dramatic increase in frequency and number of peritoneal gamma/delta T cells. Stimulation of peritoneal T cells with bacterial antigens or mitogens results in a preferential expansion of gamma/delta T cells resulting in up to 80% gamma/delta T cells in the blast population. Thus, the highly localized and inducible expression of gamma/delta T cells in the murine peritoneal cavity not only supplies evidence for the role of gamma/delta T cells in microbial immunity but also provides an excellent opportunity for elucidating the function, receptor specificity, and activation requirements of gamma/delta T cells. In this proposal, research will be aimed at understanding the mechanism(s) by which gamma/delta T cells are induced by microbial products. The proposed work will help define the receptor specificity and activation requirements relevant to gamma/delta T cells. Experimental approaches include the identification of surface markers of gamma/delta T cells by flow cytometry, the analysis of gamma/delta T cell function in vitro with special emphasis on cytokines such as IL-7 and IL-1 that promote the proliferation of gamma/delta T cells, and the identification of TCR gene usage by a panel of gamma/delta T cell hybridomas. Several fundamental aspects of gamma/delta T cell biology will be studied with hopes of understanding the role of gamma-delta T cells in immune responses to infectious agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034065-04
Application #
2429410
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1994-09-01
Project End
1999-05-31
Budget Start
1997-08-01
Budget End
1998-05-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Zakharova, Maria; Ziegler, H Kirk (2005) Paradoxical anti-inflammatory actions of TNF-alpha: inhibition of IL-12 and IL-23 via TNF receptor 1 in macrophages and dendritic cells. J Immunol 175:5024-33
Freeman, Molly M; Ziegler, H Kirk (2005) Simultaneous Th1-type cytokine expression is a signature of peritoneal CD4+ lymphocytes responding to infection with Listeria monocytogenes. J Immunol 175:394-403
Skeen, M J; Rix, E P; Freeman, M M et al. (2001) Exaggerated proinflammatory and Th1 responses in the absence of gamma/delta T cells after infection with Listeria monocytogenes. Infect Immun 69:7213-23
Zirk, N M; Hashmi, S F; Ziegler, H K (1999) The polysaccharide portion of lipopolysaccharide regulates antigen-specific T-cell activation via effects on macrophage-mediated antigen processing. Infect Immun 67:319-26
Miller, M A; Skeen, M J; Ziegler, H K (1998) Long-lived protective immunity to Listeria is conferred by immunization with particulate or soluble listerial antigen preparations coadministered with IL-12. Cell Immunol 184:92-104
Miller, M A; Skeen, M J; Ziegler, H K (1997) A synthetic peptide administered with IL-12 elicits immunity to Listeria monocytogenes. J Immunol 159:3675-9
Hiltbold, E M; Ziegler, H K (1996) Interferon-gamma and interleukin-10 have cross-regulatory roles in modulating the class I and class II MHC-mediated presentation of epitopes of Listeria monocytogenes by infected macrophages. J Interferon Cytokine Res 16:547-54
Miller, M A; Skeen, M J; Ziegler, H K (1995) Nonviable bacterial antigens administered with IL-12 generate antigen-specific T cell responses and protective immunity against Listeria monocytogenes. J Immunol 155:4817-28