Direct Regulation of CD8 T Cells by Interferon gamma

Summary

Principal Investigator: Marulasiddappa Suresh
Abstract: Arena viruses are one of the many etiologic agents of viral hemorrhagic fever (VHF) in humans. Because of the high rates of mortality and morbidity associated with these infections, and the potential of being used as agents of bioterrorism, are arenaviruses are classified under category A pathogens. At the present time, there are no vaccines to provide protection against arena viral infections in human beings. The Old World arena viruses include the Lassa virus and lymphocytic choriomeningitis virus (LCMV). Evidence indicate that cellular immunity mediated by CD8 T cells is important in defense against LCMV, and most likely Lassa virus. Therefore, vaccines against these viruses need to engender potent CD8 T cell memory. However, the mechanism(s) of induction of CD8 T cell memory are not well understood and currently, this is an area of intense investigation. Typically, CD8 T cell responses can be divided into three distinct phases: (1) the expansion phase when naive T cells undergo antigen-driven proliferation and differentiation into effector cells, (2) the contraction phase when 90-95% of the expanded T cells are eliminated, and (3) the memory phase when the remaining 5% of the expanded CD8 T cells survive for extended periods as memory T cells. The number of memory CD8 T cells generated is dependent upon the extent of expansion and the magnitude of contraction. Since protective immunity is dependent upon the induction of a threshold number of memory CD8 T cells, it is critical to gain a thorough understanding of the mechanisms that regulate the expansion and contraction phases of the T cell response. Using the well-characterized LCMV model in mice, we have obtained strong preliminary data that IFNgamma receptor (IFNgammaR) signaling plays an important role in limiting the number of antigen-specific memory CD8 T cells that survive the contraction phase of the T cell response. Based on this a strong case can be made to modulate IFNgammaR signaling to augment the number of memory CD8 T cells during vaccination. Understanding the mechanisms underlying the regulation of LCMV-specific CD8 T cell response by IFNgammaR is the focus of this proposal. The specific aims are: (1) To determine the importance of IFNgammaR expressed on T cells vs. non-T cells in regulating CD8 T cell responses in vivo by utilizing TCR transgenic mice, bone marrow chimeric mice, and IFN( unresponsive transgenic T cells, (2) To investigate the importance of temporal and spatial control of IFNgammaR signaling in the regulation of the contraction phase of LCMV-specific CD8 T cell response by antibody blocking experiments and by developing a transgenic mouse model in which IFNgammaR expression in T-cell lineage can be turned on and off at will, and (3) To determine the effect of IFNgammaR deficiency on the qualitative and functional attributes of LCMV-specific memory CD8 T cells. These studies should aid in the development of vaccines against arena viruses in particular and other viruses in general.
Funding Period: ----------------2010 - ---------------2010-
more information: NIH RePORT

Top Publications

  1. pmc Differential requirement for Lck during primary and memory CD8+ T cell responses
    Kavita Tewari
    Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA
    Proc Natl Acad Sci U S A 103:16388-93. 2006
  2. pmc T-cell intrinsic and extrinsic mechanisms of p27Kip1 in the regulation of CD8 T-cell memory
    Anna Jatzek
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, USA
    Immunol Cell Biol 91:120-9. 2013
  3. pmc Effects of IL-7 on memory CD8 T cell homeostasis are influenced by the timing of therapy in mice
    Som G Nanjappa
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, Wisconsin 53706, USA
    J Clin Invest 118:1027-39. 2008
  4. ncbi Cbl-b regulates antigen-induced TCR down-regulation and IFN-gamma production by effector CD8 T cells without affecting functional avidity
    Mohammed Shamim
    Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA
    J Immunol 179:7233-43. 2007
  5. ncbi Role of direct effects of IFN-gamma on T cells in the regulation of CD8 T cell homeostasis
    Kavita Tewari
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, WI 53706, USA
    J Immunol 179:2115-25. 2007
  6. pmc C3 promotes expansion of CD8+ and CD4+ T cells in a Listeria monocytogenes infection
    Yumi Nakayama
    Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA
    J Immunol 183:2921-31. 2009
  7. pmc Regulation of memory CD8 T-cell differentiation by cyclin-dependent kinase inhibitor p27Kip1
    Anju Singh
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, WI 53706, USA
    Mol Cell Biol 30:5145-59. 2010
  8. pmc Immunotherapeutic effects of IL-7 during a chronic viral infection in mice
    Som G Nanjappa
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, WI, USA
    Blood 117:5123-32. 2011
  9. pmc Signal integration by Akt regulates CD8 T cell effector and memory differentiation
    Eui Ho Kim
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, WI 53706, USA
    J Immunol 188:4305-14. 2012
  10. pmc Role of PKR and Type I IFNs in viral control during primary and secondary infection
    Yumi Nakayama
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, Wisconsin, United States of America
    PLoS Pathog 6:e1000966. 2010

Scientific Experts

  • Marulasiddappa Suresh
  • Yumi Nakayama
  • Som G Nanjappa
  • Anna Jatzek
  • Eui Ho Kim
  • Kavita Tewari
  • Erin H Plisch
  • Anju Singh
  • John Svaren
  • Melba Marie Tejera
  • Erin Hemmila Plisch
  • Mohammed Shamim
  • Jane Walent
  • Matthew L Fero
  • Kwan Yong Choi
  • Jeremy A Sullivan
  • Chester Thomas
  • Charles J Czuprynski
  • Jeremy Sullivan
  • Bryan R G Williams
  • Rajini Srinivasan
  • Matyas Sandor
  • John D Lambris
  • Shin Il Kim
  • Jane H Walent
  • Michel Morre
  • Scott E Leblanc
  • Christine Seroogy
  • Rose Zamoyska

Detail Information

Publications10

  1. pmc Differential requirement for Lck during primary and memory CD8+ T cell responses
    Kavita Tewari
    Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA
    Proc Natl Acad Sci U S A 103:16388-93. 2006
    ....
  2. pmc T-cell intrinsic and extrinsic mechanisms of p27Kip1 in the regulation of CD8 T-cell memory
    Anna Jatzek
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, USA
    Immunol Cell Biol 91:120-9. 2013
    ..These findings have implications in vaccine development and understanding the mechanisms that maintain T-cell homeostasis...
  3. pmc Effects of IL-7 on memory CD8 T cell homeostasis are influenced by the timing of therapy in mice
    Som G Nanjappa
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, Wisconsin 53706, USA
    J Clin Invest 118:1027-39. 2008
    ..These findings may have implications in the clinical use of IL-7 as an immunotherapeutic agent to bolster vaccine-induced CD8(+) T cell memory...
  4. ncbi Cbl-b regulates antigen-induced TCR down-regulation and IFN-gamma production by effector CD8 T cells without affecting functional avidity
    Mohammed Shamim
    Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA
    J Immunol 179:7233-43. 2007
    ..These findings have implications in the development of therapies to bolster CD8 T cell function during viral infections or suppress T cell-mediated immunopathology...
  5. ncbi Role of direct effects of IFN-gamma on T cells in the regulation of CD8 T cell homeostasis
    Kavita Tewari
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, WI 53706, USA
    J Immunol 179:2115-25. 2007
    ..These findings have clarified fundamental features of control of T cell homeostasis by IFN-gamma in the context of CD8 T cell memory and protective immunity...
  6. pmc C3 promotes expansion of CD8+ and CD4+ T cells in a Listeria monocytogenes infection
    Yumi Nakayama
    Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA
    J Immunol 183:2921-31. 2009
    ..These studies have furthered our understanding of C3-mediated regulation of T cell immunity to intracellular pathogens...
  7. pmc Regulation of memory CD8 T-cell differentiation by cyclin-dependent kinase inhibitor p27Kip1
    Anju Singh
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, WI 53706, USA
    Mol Cell Biol 30:5145-59. 2010
    ..These findings provide critical insights into the cell cycle regulation of CD8 T-cell homeostasis and suggest that modulation of p27(Kip1) could bolster vaccine-induced T-cell memory and protective immunity...
  8. pmc Immunotherapeutic effects of IL-7 during a chronic viral infection in mice
    Som G Nanjappa
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, WI, USA
    Blood 117:5123-32. 2011
    ..In summary, our results strongly suggest that IL-7 therapy is a potential strategy to bolster the quality and quantity of T-cell responses in patients with chronic viral infections...
  9. pmc Signal integration by Akt regulates CD8 T cell effector and memory differentiation
    Eui Ho Kim
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, WI 53706, USA
    J Immunol 188:4305-14. 2012
    ..These findings suggest that therapeutic modulation of Akt might be a strategy to augment vaccine-induced immunity...
  10. pmc Role of PKR and Type I IFNs in viral control during primary and secondary infection
    Yumi Nakayama
    Department of Pathobiological Sciences, University of Wisconsin Madison, Madison, Wisconsin, United States of America
    PLoS Pathog 6:e1000966. 2010
    ..Additionally, the results presented here have furthered our understanding of the immune correlates of anti-viral protective immunity, which have implications in the rational design of vaccines...