Abstract

The main focus of this project is to determine the relative contributions of the thymus and the intestine in determining the intestinal intraepithelial T lymphocyte (IEL) repertoire. We have shown that IEL can be thymus-derived and we will use this system to test the hypothesis that T cell receptor (TCR)alpha-beta IEL are selected outside of the thymus. Our preliminary results suggest that extrathymic expression of class l major histocompatibility complex (MHG) proteins is required for positive selection of TCRalpha-beta IEL. However, we do not know where and when initial TCR gene rearrangement and lEL selection occur. Thymus grafting experiments using MHC-deficient hosts and TCR transgenic mice will answer the question of whether IEL are selected in the thymus prior to trafficking to the intestine. In situ analysis in model systems will determine whether extrathymic TCR rearrangement can occur. We will also examine the role of normal flora in determining the TCRalpha-beta IEL oligoclonal repertoire. The TCR repertoire of TCRalpha-beta IEL from gnotobiotic mice will be subjected to molecular analysis to determine the influence of flora on generation of TCR junctional diversity. Finally, we will produce TCR transgenic mice expressing IEL-type gamma-delta and alpha-beta TCRs to further study selection and development of IEL. Overall, this proposal presents a comprehensive and critical analysis of thymic versus extrathymic IEL selection and the factors involved in these processes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045260-06
Application #
2518323
Study Section
Immunobiology Study Section (IMB)
Project Start
1992-09-30
Project End
1998-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030

  Publications

Marzo, Amanda L; Yagita, Hideo; Lefrancois, Leo (2007) Cutting edge: migration to nonlymphoid tissues results in functional conversion of central to effector memory CD8 T cells. J Immunol 179:36-40
Blair, David A; Lefrancois, Leo (2007) Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells. Proc Natl Acad Sci U S A 104:15045-50
Turner, Damian L; Cauley, Linda S; Khanna, Kamal M et al. (2007) Persistent antigen presentation after acute vesicular stomatitis virus infection. J Virol 81:2039-46
Zammit, David J; Turner, Damian L; Klonowski, Kimberly D et al. (2006) Residual antigen presentation after influenza virus infection affects CD8 T cell activation and migration. Immunity 24:439-49
Myers, Lara; Lee, Seung Woo; Rossi, Robert J et al. (2006) Combined CD137 (4-1BB) and adjuvant therapy generates a developing pool of peptide-specific CD8 memory T cells. Int Immunol 18:325-33
Klonowski, Kimberly D; Marzo, Amanda L; Williams, Kristina J et al. (2006) CD8 T cell recall responses are regulated by the tissue tropism of the memory cell and pathogen. J Immunol 177:6738-46
Zammit, David J; Cauley, Linda S; Pham, Quynh-Mai et al. (2005) Dendritic cells maximize the memory CD8 T cell response to infection. Immunity 22:561-70
Marzo, Amanda L; Klonowski, Kimberly D; Le Bon, Agnes et al. (2005) Initial T cell frequency dictates memory CD8+ T cell lineage commitment. Nat Immunol 6:793-9
Klonowski, Kimberly D; Lefrancois, Leo (2005) The CD8 memory T cell subsystem: integration of homeostatic signaling during migration. Semin Immunol 17:219-29
Schluns, Kimberly S; Nowak, Elizabeth C; Cabrera-Hernandez, Arturo et al. (2004) Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor alpha expression. Proc Natl Acad Sci U S A 101:5616-21

Showing the most recent 10 out of 41 publications