Molecular Mechanisms in TCR Reactivity to Self Ligands

Summary

Principal Investigator: STEPHEN JAMESON
Affiliation: University of Minnesota
Country: USA
Abstract: Recent data lead to the intriguing conclusion that both immature and mature T-cells have the capacity to make a response to self peptide/MHC ligands. Indeed, these experiments find that such interactions are required for T-cell development and also mature T-cell homeostasis and survival. Furthermore, recent findings show that many but not all naive T-cells can respond, via proliferation and differentiation, toward self peptide/MHC ligands in conditions where total T-cell numbers are low (i.e. in lymphopenic animals). This proliferative process has been called T-cell homeostatic expansion (HME). Such data raise the question of how T-cell survival and HME are regulated to prevent loss of useful T-cell at one extreme and overt autoreactivity at the other. In this proposal, we will explore the nature of the extracellular and intracellular factors which support T-cell survival and T-cell homeostatic expansion. Four components will be studied, the TCR, cytokines, bcl-2 family proteins and a transcription factor, Lung kruppel-like factor (LKLF). Three aims are proposed. 1. Defining a T-cell's sense of space: HME only occurs in the absence of other T-cells - our hypothesis is that cytokines determine space "perception" and that the affinity of the TCR for self MHC ligands can influence IL-7 reactivity. 2. Testing bel-2 family members as substitutes for cytokin and/or TCR in homeostatic expansion: Bc1-2 proteins protect against cell death and can substitute for cytokines in T-cell development and survival. We hypothesize that bcl-2 can also substitute for cytokines and/or TCR signals in HME. 3. Role of LKLF in T-cell homeostasis: To better understand LKLF function, we will generate an LKLF transgenic mouse, and test the theory that LKLF is a master regulator of naive T ceil survival and HME. The long-term aims of this application are to understand the way in which useful T-cells are maintained in the body long term and how mature T-cells can be repopulated in cases of T lymphopenia. This has health implications for recovery of the T-cell pool in patients suffering from T lymphopenia due to disease (e.g. AIDS), or therapeutic treatments (such as bone morrow transplant).
Funding Period: 1996-07-01 - 2006-05-31
more information: NIH RePORT

Top Publications

  1. pmc T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells
    Michael A Weinreich
    The Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
    Nat Immunol 11:709-16. 2010
  2. pmc Programming for CD8 T cell memory development requires IL-12 or type I IFN
    Zhengguo Xiao
    Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
    J Immunol 182:2786-94. 2009
  3. ncbi Characteristics of NK cell migration early after vaccinia infection
    Martin Prlic
    Center for Immunology, University of Minnesota, Minneapolis 55455, USA
    J Immunol 175:2152-7. 2005
  4. pmc KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors
    Michael A Weinreich
    Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
    Immunity 31:122-30. 2009

Detail Information

Publications4

  1. pmc T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells
    Michael A Weinreich
    The Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
    Nat Immunol 11:709-16. 2010
    ..Our findings identify a previously unknown mechanism of regulation of CD8(+) T cells via the production of IL-4 by PLZF(+) T cells...
  2. pmc Programming for CD8 T cell memory development requires IL-12 or type I IFN
    Zhengguo Xiao
    Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
    J Immunol 182:2786-94. 2009
    ..These data demonstrate that IL-12 and type I IFN play an essential early role in determining whether Ag encounter by naive CD8 T cells results in formation of a protective memory population...
  3. ncbi Characteristics of NK cell migration early after vaccinia infection
    Martin Prlic
    Center for Immunology, University of Minnesota, Minneapolis 55455, USA
    J Immunol 175:2152-7. 2005
    ..These features are similar to those found for Ag-experienced T cells, suggesting similar patterns of trafficking and proliferation for these lymphocyte subsets...
  4. pmc KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors
    Michael A Weinreich
    Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
    Immunity 31:122-30. 2009
    ..Our findings support a model where KLF2 regulates T cell trafficking by direct regulation of S1P(1) and CD62L and restrains spontaneous cytokine production in naive T cells...