Peter D. Katsikis Professor, Microbiology and Immunology Ph.D., 1990, University of Ioannina, Ioannina, Greece M.D., 1985, University of Thessaloniki, Greece 2900 Queen Lane Philadelphia, PA 19129 Tel: 215-991-8380 Fax: 215-848-2271 Email: peter.katsikis@drexelmed.edu

Research Staff: Yvonne Mueller, Ph.D., Alina Boesteanu, Ph.D., Guibin Yang, Ph. D., Jill Norton, Duc Do
Graduate Students: Christy Bucks

Keywords:

HIV, CD8+ T cells, CTL, influenza virus, viruses, cytokines, apoptosis, rheumatoid arthritis

Research Interests

Our laboratory investigates the roles that cytokines, T cells, and apoptosis play in anti-viral immune responses and autoimmunity. A major focus of the laboratory is cytotoxic CD8+ T cells, which can kill other cells and play an important role in controlling viral infections. The costimulation and cytokine requirements for generation of effector and memory cytotoxic CD8+ T cells are being investigated.

Human Immunodeficiency virus (HIV)-related studies.
A number of approaches are being taken in the lab to understand and characterize the function of HIV-specific CD8+ T cells in patients with HIV infection and to elucidate their costimulation and cytokine requirements for maximal functionality.  We have recently found that HIV-specific CD8+ T cells are very susceptible to Fas/CD95-induced apoptosis and can be killed by HIV-infected cells.  This increased susceptibility to apoptosis may affect their ability to behave as serial killers in the body and ultimately impair the anti-viral function. The lab is currently working on the mechanisms behind the apoptosis sensitivity of HIV-specific CD8+ T cells and ways that may increase the survival and function of these cells.  Animal studies have shown that these defects are driven by antigen and appear very early during infection.
Studies with SIV-infected non-human primates are investigating the mechanism by which IL-15 treatment during acute SIV infection increases viral set point in animals.  These studies have established a novel model by which viral set point can be altered and this may allow us to further investigate what controls viral set point in animals.  We have also found that combination therapy between IL-15 and antiretrovirals during chronic SIV infection restores blood effector memory CD4+ T cells in animals and this may be an important approach for immune restoration during infection.

Influenza type A virus studies.
Immunity.  Using a model of Influenza type A virus infection in mice, we are investigating the in vivo regulation and costimulation requirements of cytotoxic anti-viral CD8+ T cell responses.  The roles of cytokines and costimulation molecules in the generation and regulation of primary, secondary, and memory anti-viral CD8+ T cell responses are being examined.  Finally, how dendritic cells initiate and regulate cytotoxic CD8+ T cell responses is also being explored.

Pathogenesis.  What pathogenic mechanisms that are at action during influenza virus infection are poorly understood. We are investigating the mechanisms that underlie the morbidity associated with influenza virus infection and are dissecting the triggers that lead to inflammation and disease.  An understanding of the pathogenic process may allow us to develop novel treatments for pandemic and seasonal influenza virus infections.

Vaccine development.  Vaccines that elicit CD8+ T cell responses against influenza virus have the potential to act as “universal” vaccines that provide broad protection against multiple strains of influenza virus.  For this purpose we are developing novel vaccine approaches that potently stimulate a CD8+ T cell response against influenza virus and may reduce the morbidity and mortality of potential pandemic and seasonal strains of influenza virus infection.

Selected Publications

1. Mueller, Y. M., De Rosa, S., Hutton, J. A., Witek, J., Roederer, M., Altman, J. D., and P. D. Katsikis.  Increased CD95/Fas induced apoptosis of HIV-specific CD8+ T cells.  Immunity 15: 1-20, 2001.
   
   
2. Halstead, S. E., Mueller, Y. M., Altman, J. D., and P. D. Katsikis.  In vivo stimulation of CD137 broadens primary antiviral CD8+ T cell responses.  Nature Immunology, 3: 536-541, 2002.
   
   
3. Mueller, Y.M., Bojczuk, P., Witek, J., Altman, J. D., and P. D. Katsikis.  IL-15 enhances survival and function of HIV-specific CD8+ T cells.  Blood 101: 1024-1029, 2003.
   
   
4. Petrovas, C., Mueller, Y. M., Dimitriou, I. D., Bojczuk, P. M., Mounzer, K. C., Witek, Altman, J. D., and P. D. Katsikis.  HIV-specific CD8+ T cells exhibit markedly reduced levels of Bcl-2 and Bcl-xL.  Journal of Immunology, 172: 4444-4453, 2004.
   
   
5. Kim, A. H. J., Dimitriou, I. D., Holland, M. C. H., Mastellos, D., Mueller, Y. M., Altman, J. D., Lambris, J. D., and P. D. Katsikis.  Complement C5aR is essential for the optimal generation of antiviral CD8+ T cell responses.  Journal of Immunology, 173: 2524-2529, 2004.
   
   
6. Mueller, Y. M., Petrovas, C., Bojczuk, P., Dimitriou, I. D., Beer, B., Silvera, P., Villinger, F., Cairns, J. S., Gracely, E., Lewis, M. G., and P. D. Katsikis.  IL-15 increases effector memory CD8+ T cells and NK cells in SIV-infected macaques.  J. Virol., 79: 4877-4885, 2005.
   
   
7. Dolfi, D. V. and P. D. Katsikis.  CD28 and CD27 costimulation of CD8+ T cell responses: A story of survival.  Adv. Exp. Med. Biol., 590: 149-170, 2007.
   
   
8. Petrovas, C., Mueller, Y. M., Dimitriou, I. D., Altork, S. R., Banerjee, A., Sklar, P., Mounzer, K. C., Altman, J. D., and P. D. Katsikis.  Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells.  Blood, 109: 2505-2513, 2007.
   
   
9. Mueller, Y. M., Petrovas, C., Dimitriou, I. D., Altman, J. D., Lewis, M. G., and P. D. Katsikis.  SIV-specific CD8+ T cells exhibit increased apoptosis sensitivity and skewed memory phenotype similar to HIV-specific CD8+ T cells.  J. Virol., 81: 10861-10868, 2007.
   
   
10. Petrovas, C., Mueller, Y. M., Altork, S. R., Jacobson, J. M., Pitsakis, P. G., Mounzer, K. C., Altman, J. D., and P. D. Katsikis.  Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells.  Apoptosis, 12: 2175-2186, 2007.
    
    
11. Katsikis, P. D., Schoenberger, S. P., and B. Pulendran.  Probing the 'labyrinth' linking the innate and adaptive immune systems.  Nat Immunol., 8: 899-901, 2007.
    
    
12. Borowski, A. B., Boesteanu, A. C., Mueller, Y. M., Carafides, C., Altman, J. D., Jennings, S. R., and P. D. Katsikis.  Memory CD8+ T cells require CD28 costimulation.  J. Immunol., 179: 6494-6503, 2007.
    
    
13. Mueller, Y.M., Duc, D. H., Altork, S. R., Artlett, C. M., Gracely, E. J., Katsetos, C. D., Legido, A., Villinger, F., Altman, J. D., Brown, C. R., Lewis, M. G., and P. D. Katsikis.  IL-15 treatment during acute SIV infection increases viral set point and accelerates disease progression despite the induction of stronger SIV-specific CD8+ T cell responses.  J Immunol., 180: 350-360, 2008.
    
    
14. Dolfi, D. V., Boesteanu, A. C., Petrovas, C., Xia, D., Butz, E. A., and P. D. Katsikis.  Late signals from CD27 prevent Fas dependent apoptosis of primary CD8+ T cells.  J. Immunol., 180: 2912–2921, 2008.