Katherine Kedzierska BSc (Hons) PhD

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Include: Bio | Academic degrees | Professional appointments | Research Interests | Recent Publications (2007 — present)

Bio

Dr Kedzierska trained as a viral immunologist and has over 14 years of experience in researching the immune responses to acute (influenza) and chronic (HIV) viral infections. Her expertise in both the murine system and human settings allows her to translate any of the key findings obtained from an easily manipulated mouse model into human viral immunology. Her PhD work undertaken at the Burnet Institute in Melbourne has provided an important contribution to our knowledge of AIDS pathogenesis by proposing the mechanisms of why HIV-infected patients develop specific opportunistic infections as their disease progresses, ultimately the cause of their death. Her PhD work was recognised by prestigious awards, including a 2001 Premier’s Commendation for Medical Research, 2002 Monash University Mollie Holman Doctoral Medal for the Best PhD Thesis and the NHMRC Peter Doherty Postdoctoral Fellowship to pursue her postdoctoral research with Nobel Laureate Professor Peter Doherty. She joined Professor Doherty’s laboratory upon his return to the Department of Microbiology and Immunology at the University of Melbourne in July 2002. During the four-year postdoctoral position she has further contributed to the field of viral immunology and developed her own research interests related to the cellular and molecular aspects of CD8+ T cell immunity to influenza virus infection. After being awarded the NHMRC RD Wright Fellowship and a NHMRC Project Grant, she established her independent research group in the Department of Microbiology and Immunology. She aims to understand how immunological T cell memory is generated, whether it is feasible to elicit immunity towards escape viral variants, and how T cell receptor repertoire relates to T cell phenotype, function and viral escape.

Dr Kedzierska also has an immense interest in mentoring junior scientist. She facilitates the promotion of outstanding young scientists via her role as a co-convenor of the Premier’s Award for Medical Research (the state’s most prestigious award for emerging young scientists) and the convenor of two annual Departmental PhD awards: the QIAGEN PhD Achievement Award and the Pfizer PhD Oration Award.

Academic Degrees:

1995: BSc (Hons), Monash University, Clayton, Australia
2002: PhD, Monash University, Clayton, Australia

Professional Appointments:

Research Interests

How is the immunological T cell memory generated?

Memory cells are of an immense importance for the generation of protection against recurrent infections, therefore an important factor for the development of new vaccine candidates and improvement of already existing vaccines. However, the molecular and differentiation pathways central to the generation, maintenance and recall of CD8+ T cell memory are still far from clear. Our studies showed for the first time that immunological memory is generated within three days after influenza infection, preferentially in the draining lymph nodes. These findings shifted the paradigm for generation of immunological memory. Now we aim to understand the mechanisms underlying early establishment of T cell memory and its maintenance. The key questions of the current research program are:

1. what determines that a particular T cell at the onset of influenza virus infection becomes a memory rather than effector T cell
2. what are the molecular mechanisms involved in the process of memory formation
3. how do these early generated memory cells offer life-long protection, especially in the aged population.

Our hypothesis is that by providing the optimal stimulation, we can increase the number of life-lasting influenza-specific memory CD8+ T cells, thereby improving protection against recurrent infections. Since generation of memory cells is one of the key questions in viral immunology, the outcomes of this work will lead to improved understanding of antiviral immunity and facilitate development of successful vaccines.

Personnel: Dr Kedzierska, Ms Hayley Croom and Ms Sophie Valkenburg

The mechanisms of viral escape in murine and human influenza infection

CD8+ T cells play a critical role in the control of virus infections. In influenza, CD8+ T cell-mediated cross-protection against different viral strains might, in the face of a pandemic, ameliorate the disease sufficiently to promote survival rather than death. However, the resultant CD8+ T cell responses exert selective pressure on viruses, leading to the possibility of escape mutations in viral peptides. Virus escape mutants constitute a major problem for CD8+ T cell-mediated control and vaccine design in persistent (LCMV, HIV, HCV, HBV, SIV) and acute (influenza) infections. To date, the extent of viral escape within influenza T cell epitopes (mutations occur in 71.4% of human T cell epitopes) has not received much attention. In seasonal influenza infection, escape from existing CD8+ T cell responses is particularly relevant to persistence of the virus within the population. In the face of a pandemic, it would lead to a total lack of CD8+ T cell cross-protection in individuals with specific HLA alleles. Thus, it is critical to understand the mechanisms of viral escape in influenza and investigate any possible compensatory strategies. Our research aims to provide insights into the CD8+ T cell escape mutants that can emerge in RNA virus infections, with the ultimate aim of improving vaccine design. We investigate mechanisms of viral escape in an easily manipulated mouse model of influenza infection, and further verify the key findings in humanised transgenic HLA-A2 mice and human peripheral blood mononuclear cells. A combination of sophisticated cellular and molecular immune assays, access to the WHO Centre database of 30,000 human influenza isolates and structural studies will help us to understand:

1. the emergence of influenza viral variants
2. the availability/efficacy of CD8+ T cells to recognise the emerging mutants
3. any structural constraints that may limit (i)&(ii).

This work will enhance our understanding of the mechanisms underlying viral escape that are critical for T cell-based protective immunity and vaccine design against influenza, persistent virus infections and tumours.

Personnel: Dr Kedzierska and Ms Sophie Valkenburg

Tracking phenotypically and functionally distinct T cell subsets via T cell repertoire diversity

T cell receptor (TCR) diversity influences both the protective capacity of CD8+ T cells and the subversion of immune control that leads to viral escape. The spectrum of TCR selection and maintenance has implications for improving the functional efficacy of T cell responsiveness and effector function. We are using the cutting edge single-cell PCR technology to understand the factors that determine diversity of T cells responding to a particular antigen. This is critical to our understanding of antiviral immunity. Furthermore, based on the specific TCR signatures of CD8+ T cells at different stages of viral infection, we are able to track distinct subsets of effector and memory CD8+ T cells. Based on the expression of markers such as CD62L, IL-7R, KLRG-1, CD27 and CD43, we aim to understand the fate of particular T cell clones expressing different phenotypic and/or functional characteristics during the immune response. This allows us to make a thorough dissection of antiviral immunity at the clonal level.

Personnel: Dr Kedzierska and Ms Natasha Swan

Recent Publications (2007 — present)

Original Articles

1. Kedzierski L, Curtis JM, Kedzierska K. Early CD44hiCD4+ and CD44hiCD8+ T cell numbers and the absence of mannose-rich glycoconjugates determine the protective outcome of antileishmanial immunity. Parasitology, 2009 (in press).
2. Kedzierski L, Sakthianandeswaren A, Junk PC, Andrews PC, Curtis JM, Kedzierska K. Leishmanisis: current treatment and prospects for new drugs and vaccines. Curr Med Chem 2009; 16: 599-614.
3. Schlub T, Venturi V, Kedzierska K, Wellard C, Doherty PC, Turner SJ, Ribeiro RM, Hodgkin PD, Davenport MP. Division-linked differentiation can account for CD8+ T cell phenotype in vivo. EJ Immunol 2009; 39: 67-77.
4. Brown LE, Deliyannis G, Kedzierska K, Lau YF, Ng WC, Zeng W, Petruccelli M, Gilbertson B, Lim B, Cobbin J, Kelso A, Turner SJ, Jackson DC. Lipopeptide vaccines illustrate the potential role of subtype-crossreactive T cell responses in the control of seasonal and pandemic influenza. In: Options in Influenza IV. Katz et al. Eds. Elsevier, Amsterdam. International Congress Series, 199-201, 2008.
5. Jenkins MR, Mintern J, La Gruta NL, Kedzierska K, Doherty PC, Turner SJ. Cell-cycle related acquisition of cytotoxic mediators defines the progressive differentiation to effector status for virus-specific CD8+ T cells. J Immunol 2008; 181: 3818-22.
6. Stambas J, Guillonneau C, Kedzierska K, Mintern, J Doherty PC, La Gruta NL. Killer T Cells in Influenza. Pharmacology " Therapeutics 2008; 120: 186-96.
7. Kedzierski L, Curtis JM, Doherty PC, Handman E, Kedzierska K. Decreased IL-10 and IL-13 production and increased CD44hi T cell recruitment contribute to Leishmania major immunity induced by non-persistent parasites. Eur J Immunol 2008; 38: 3090-3100.
8. Rollman E, Turner SJ, Kedzierska K, Kent SJ. Anti-SIV cytolytic molecules in pigtail macaques. ARHR 2008; 24: 1127-31.
9. Venturi V, Kedzierska K, Tanaka MM, Turner SJ, Doherty PC, Davenport MP. Methods for assessing the similarity between subsets of the T cell receptor repertoire. J Immunol Meth 2008; 329: 67-80.
10. Kedzierska K, Thomas PG, Venturi V, Davenport MP, Doherty PC, Turner SJ, La Gruta NL. Terminal Deoxynucleotidyltransferase is required for the establishment of private virus-specific CD8+ TCR repertoires and facilitates optimal CTL responses. J Immunol 2008; 181: 2556-62.
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11. Kedzierska K, Venturi V, Valkenburg SA, Davenport MP, Turner SJ, Doherty PC. Homogenization of TCR repertoires within secondary effector and memory virus-specific CD8+ T cells. J Immunol 2008; 180: 7938-47.
12. Kedzierska K, La Gruta NL, Stambas J, Turner. SJ, Doherty PC. Tracking of phenotypically and functionally distinct T cell subsets via T cell receptor repertoire. Mol Immunol 2008; 45: 607-18.
13. Kedzierska K, Guillonneau C, Hatton LA, Stockwell D, Gras S, Webby R, Rossjohn J, Purcell AW, Doherty PC, Turner SJ. Complete modification of TCR specificity and repertoire selection does not perturb a CD8+ T cell immunodominance hierarchy. PNAS 2008; 105: 19408-13.
14. La Gruta NL, Kedzierska K, Stambas J, Doherty PC. A question of self-preservation: immunopathology in influenza virus infection. Immunol & Cell Biol 2007; 85: 85-92.
15. Day EB, Zeng W, Doherty PC, Jackson DC, Kedzierska K, Turner SJ. The context of epitope presentation can influence functional quality of recalled Influenza A virus-specific memory CD8+ T cells. J Immunol 2007; 179: 2187-94
16. Jenkins M, Kedzierska K, Doherty PC, Turner SJ. Heterogeneity of effector phenotype for acute phase and memory influenza A virus-specific CTL. J Immunol 2007; 179: 64-70.
17. Venturi V, Kedzierska K, Turner SJ Doherty PC, Davenport MP. Methods for comparing the diversity of samples of the T cell receptor repertoire. J Immunol Meth 2007; 321: 182-95.
18. Kedzierska K, Stambas J, Jenkins M, Keating R, Turner SJ, Doherty PC. Location rather than CD62L phenotype is critical in the early establishment of influenza-specific CD8+ T cell memory. Proc Nat Acad Sci USA 2007; 104: 9782-87.