IMMUNOBIOLOGY OF INTESTINAL INTRAEPITHELIAL LYMPHOCYTES

Summary

Principal Investigator: Leo Lefrancois
Affiliation: University of Connecticut Health Center
Country: USA
Abstract: The overall aim of this proposal is to study the developmental biology of a major arm of the mucosal immune system, namely, intraepithelial lymphocytes (IEL). There are three major goals of our studies. 1) To study the mechanism of selection of V64+ murine IEL. Analysis of T cell receptor (Tcr) junctional diversity and the relative contribution of the two V-delta-64 genes will be performed. Recombinant inbred and backcross mice will be used to map the element(s) involved in the selection process. This system offers an excellent opportunity to analyze the in vivo mechanism of gamma delta T cell selection and will lead to a better understanding of gamma delta T cell specificity and function. 2)To study the differentiation pathway of IEL. The intestine may be a site of extrathymic T cell development. If true, precursors of IEL, and perhaps other T cells, may reside in the intestinal mucosa. Reconstitution of severe combined immunodeficient mice (SCID) using IEL and thymocyte subsets will be performed in order to address this possibility. Additionally, recombination activating gene (RAG) expression will be determined in IEL subsets as a further measure of maturational stage. A second site of T cell maturation may be important for organ-specific immunity and could be a potential source of autoimmune reactivity. 3)To determine Tcr V region, usage and function in IEL subsets. "Forbidden" alpha-beta Tcrs are expressed on a subset of IELs but a complete analysis of V region usage in all IEL subsets has not been performed. Fluorescence flow cytometry will be used to analyze V region expression of IEL subsets including CD4+8+ IELs. Most importantly, the functional qualities of non-deleted IEL will be tested. In conjunction with the reconstitution experiments the influence of the thymus on the expression of "forbidden" Tcrs will be assessed. Considering the potential importance of the mucosal immune system in the etiology of intestinal autoimmune disorders and in combatting infectious diseases it is imperative to obtain a detailed understanding of the control of mucosal T cell development and function. The experiments proposed will significantly further our knowledge in this area.
Funding Period: 1992-09-30 - 1995-09-29
more information: NIH RePORT

Top Publications

  1. ncbi The CD8 memory T cell subsystem: integration of homeostatic signaling during migration
    Kimberly D Klonowski
    Division of Immunology, Department of Medicine, University of Connecticut Health Center, M/C 1319, 263 Farmington Avenue, Farmington, CT 06030-1319, USA
    Semin Immunol 17:219-29. 2005
  2. ncbi Dendritic cells maximize the memory CD8 T cell response to infection
    David J Zammit
    Division of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA
    Immunity 22:561-70. 2005
  3. ncbi Initial T cell frequency dictates memory CD8+ T cell lineage commitment
    Amanda L Marzo
    Division of Immunology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
    Nat Immunol 6:793-9. 2005
  4. ncbi Combined CD137 (4-1BB) and adjuvant therapy generates a developing pool of peptide-specific CD8 memory T cells
    Lara Myers
    Department of Immunology, School of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
    Int Immunol 18:325-33. 2006
  5. ncbi Residual antigen presentation after influenza virus infection affects CD8 T cell activation and migration
    David J Zammit
    Department of Immunology, University of Connecticut Health Center, Farmington, 06032, USA
    Immunity 24:439-49. 2006
  6. ncbi CD8 T cell recall responses are regulated by the tissue tropism of the memory cell and pathogen
    Kimberly D Klonowski
    Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030 1319, USA
    J Immunol 177:6738-46. 2006
  7. ncbi Persistent antigen presentation after acute vesicular stomatitis virus infection
    Damian L Turner
    Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030 1319, USA
    J Virol 81:2039-46. 2007
  8. ncbi Cutting edge: migration to nonlymphoid tissues results in functional conversion of central to effector memory CD8 T cells
    Amanda L Marzo
    Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
    J Immunol 179:36-40. 2007
  9. ncbi Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells
    David A Blair
    Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030 1319, USA
    Proc Natl Acad Sci U S A 104:15045-50. 2007

Detail Information

Publications9

  1. ncbi The CD8 memory T cell subsystem: integration of homeostatic signaling during migration
    Kimberly D Klonowski
    Division of Immunology, Department of Medicine, University of Connecticut Health Center, M/C 1319, 263 Farmington Avenue, Farmington, CT 06030-1319, USA
    Semin Immunol 17:219-29. 2005
    ..Moreover, we hypothesize that the process of acquisition of homeostatic signals in specific tissues, such as the cytokines IL-7 and IL-15, regulates the mobility of memory T cells...
  2. ncbi Dendritic cells maximize the memory CD8 T cell response to infection
    David J Zammit
    Division of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA
    Immunity 22:561-70. 2005
    ..These data show that interaction with DCs is a major mechanism driving T cell reactivation in vivo, even during a tissue-specific infection of the respiratory tract...
  3. ncbi Initial T cell frequency dictates memory CD8+ T cell lineage commitment
    Amanda L Marzo
    Division of Immunology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
    Nat Immunol 6:793-9. 2005
    ..These findings do not adhere to the present dogma regarding memory T cell generation and provide a means for identifying factors controlling memory T cell lineage commitment...
  4. ncbi Combined CD137 (4-1BB) and adjuvant therapy generates a developing pool of peptide-specific CD8 memory T cells
    Lara Myers
    Department of Immunology, School of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
    Int Immunol 18:325-33. 2006
    ..Taken together, the data indicate that CD137 and adjuvant combined therapy is an efficacious vaccine strategy for immunization with non-replicating inert antigen...
  5. ncbi Residual antigen presentation after influenza virus infection affects CD8 T cell activation and migration
    David J Zammit
    Department of Immunology, University of Connecticut Health Center, Farmington, 06032, USA
    Immunity 24:439-49. 2006
    ..These data show that antigen that is retained after pulmonary influenza virus infection controls the migratory pattern and activation state of virus-specific CD8 T cells near the site of virus amplification...
  6. ncbi CD8 T cell recall responses are regulated by the tissue tropism of the memory cell and pathogen
    Kimberly D Klonowski
    Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030 1319, USA
    J Immunol 177:6738-46. 2006
    ..Our findings indicated that characteristics of the infectious agent and the migratory preferences of memory cells dictated the secondary lymphoid tissue requirement for the recall response to infection...
  7. ncbi Persistent antigen presentation after acute vesicular stomatitis virus infection
    Damian L Turner
    Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030 1319, USA
    J Virol 81:2039-46. 2007
    ..These findings suggested that protracted antigen presentation after an apparently acute virus infection may contribute to an ongoing antiviral immune response...
  8. ncbi Cutting edge: migration to nonlymphoid tissues results in functional conversion of central to effector memory CD8 T cells
    Amanda L Marzo
    Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
    J Immunol 179:36-40. 2007
    ..Contemporaneously, the costimulator CD27 was down-regulated. These findings hold important implications for memory cell lineage development and tissue-specific immunity...
  9. ncbi Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells
    David A Blair
    Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030 1319, USA
    Proc Natl Acad Sci U S A 104:15045-50. 2007
    ..Moreover, the induction of effector function was concomitantly inhibited. Thus, competition for antigen during CD4 T cell priming is a major contributing factor to the development of the memory CD4 T cell pool...