Research Topics

Species

PERIPHERAL CD8+ T CELL TOLERANCE

Summary

Principal Investigator: Linda Sherman
Affiliation: The Scripps Research Institute
Country: USA
Abstract: DESCRIPTION (provided by applicant): In a healthy individual, the immune system uses several different immune tolerance mechanisms in order to prevent the development of autoimmune disease. For T cells, these include thymic and peripheral mechanisms that result in elimination of autoreactive cells, such as receptor editing and deletion, as well as other mechanisms that allow T cells with potentially autoreactive T cell receptors (TCR) to remain as part of the TCR repertoire but to be controlled in their ability to respond. The latter include inhibitory mechanisms that act intrinsically to the cell, generally referred to as anergy;and mechanisms that regulate extrinsically, through the activity of regulatory T cells. Little is known about the underlying mechanism responsible for whether a self-reactive CD8 T cell in the periphery undergoes tolerance through deletion or anergy. Studies in this proposal will delineate the molecular pathways through which peripheral tolerance of na[unreadable]ve CD8 cells occurs. Aim 1 will test the hypothesis that T cell receptor affinity determines whether tolerance occurs through anergy or deletion. The affinity of CD8 T cell activation will be varied using well-defined altered peptide ligands. We will also determine whether the tolerance mechanism induced through T cell recognition of antigen on cross-presenting dendritic cells in vivo depends upon the strength of TCR signaling. Preliminary data obtained through microarray analysis of gene expression in cells undergoing deletion and anergy has revealed a number of transcriptional features unique to each tolerance mechanism that form the basis for Aims 2 and 3 in this proposal. Aim 2 will examine the molecular pathways that are responsible for T cell deletion. We will test the hypothesis that deletion occurs as the result of induction of the tumor suppressors genes, GADD45g and FHIT. These may contribute to activation of the proapoptotic Bim through stress induced MAP kinases. This will be tested by inactivating the components of these pathways through the use of genetically deficient mice and pharmacological inhibitors. Aim 3 will test the hypothesis that the mechanism of anergy that occurs when na[unreadable]ve CD8 cells are activated with a high dose of toleragen involves enhanced expression of one or more negative costimulatory molecules, including;PD-1, NKG2a and Semaphorin 7A. PUBLIC HEALTH RELEVANCE: Understanding and enforcing immune tolerance mechanisms is important in preventing autoimmune diseases and in preventing graft rejection. The goal of this proposal is to further our understanding of molecular mechanisms that underlie immune tolerance so that we may develop new drugs and interventions that will help to prevent these diseases.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. ncbi N-terminal trimer extension of nominal CD8 T cell epitopes is sufficient to promote cross-presentation to cognate CD8 T cells in vivo
    Cheng Hong Wei
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    J Immunol 179:8280-6. 2007
  2. ncbi Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells
    S B Justin Wong
    Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA
    J Immunol 180:3122-31. 2008
  3. ncbi The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen
    William L Redmond
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    J Immunol 180:5275-82. 2008
  4. pmc PTPN22 Controls the Germinal Center by Influencing the Numbers and Activity of T Follicular Helper Cells
    Christian J Maine
    Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037
    J Immunol 192:1415-24. 2014

Detail Information

Publications4

  1. ncbi N-terminal trimer extension of nominal CD8 T cell epitopes is sufficient to promote cross-presentation to cognate CD8 T cells in vivo
    Cheng Hong Wei
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    J Immunol 179:8280-6. 2007
    ..This method of peptide extension should prove of great value in facilitating in vivo studies of CD8 immunity and tolerance that rely on cross-presentation...
  2. ncbi Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells
    S B Justin Wong
    Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA
    J Immunol 180:3122-31. 2008
    ....
  3. ncbi The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen
    William L Redmond
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    J Immunol 180:5275-82. 2008
    ..Taken together, these data reveal that initiation of clone 4 T cell apoptosis during the induction of peripheral tolerance to a cross-presented self-Ag occurs through a Bcl-2-sensitive and at least partially Bim-dependent mechanism...
  4. pmc PTPN22 Controls the Germinal Center by Influencing the Numbers and Activity of T Follicular Helper Cells
    Christian J Maine
    Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037
    J Immunol 192:1415-24. 2014
    ..This is evident in the KBxN mouse model of arthritis in which PTPN22 deficiency results in increased severity of disease. Our findings demonstrate the importance of cell type-specific PTPN22 activity on regulation of Ab production. ..