La Gruta Laboratory
Page Contents
Include: Research Interests | Research Staff | Recent Publications
Associate Professor Nicole La Gruta BSc (Hons) PhD
| Academic Degrees | Contact Details | |
| 1995: BSc (Hons), Monash University, Clayton, Australia 2000: PhD, Monash University |
Tel: +61 3 8344 7962 Fax: +61 3 8347 1540 Email: nllg@unimelb.edu.au Room 3.12A, Department of Microbiology and Immunology |
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| Professional Appointments |
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| 2007 — present: NH&MRC RD Wright Fellow, Department of Microbiology and Immunology | ||
Research Interests
Dr Nicole La Gruta
The role of TNFα in promoting CD8+ T cell function following influenza virus infection
TNF-α is a pro-inflammatory cytokine produced following virus infection by cells of the innate immune system as well as virus-specific CD8+ T cells. A large proportion of influenza epitope-specific CD8+ T cells produce TNF-α, and in vitro data has shown it to be the first cytokine produced by these cells after activation. TNF-α has been described as an important mediator of both viral clearance as well as virus induced immunopathogenesis. In this project we aim to determine the role of total TNF-α, and specifically the role of CD8+ T cell derived-TNF-α, in mediating clearance of influenza virus and the function and localization of virus-specific CD8+ T cells following infection. To this end, we are infecting mice lacking TNF-α (TNF-α-/- mice) with influenza A virus to analyse the virus-specific CD8+ T cell responses following primary infection, into the memory phase, and then upon subsequent virus challenge. In addition, we are transferring CD8+ T cells derived from TNF-α-/- mice into normal mice to determine the specific role of CD8+ T cell derived-TNF-α in mediating viral clearance and CD8+ T cell function. Together, these studies will provide important insights into the relative roles of TNF-α derived from the innate immune system or virus-specific CD8+ T cells, on CD8+ T cell function and viral clearance following influenza virus infection.
Enumeration and characterization of naïve epitope-specific CD8+ T cell populations
Little is known about the principal determinants of immune magnitude during anti-viral CTL responses. In particular, the question of how the characteristics of naïve epitope-specific CD8+ T cell precursors (CTLps) influence the immune response is poorly studied, largely due to the difficulty of detecting these extremely low frequency peptide + MHC class I (pMHCI)-specific T cells prior to antigen-driven expansion. Recently, a tetramer-based magnetic enrichment technique has been developed to enable the direct detection of pMHCI epitope-specific T cells in naïve mice. We are utilizing this technique to directly enumerate naïve CTLps specific for multiple influenza virus epitopes in B6 mice, and to characterize the T cell receptor repertoires contained within the naïve populations. These findings will directly impact rational vaccine design by defining the quantitative and qualitative potential of naïve epitope-specific CTL repertoires. Such insights are essential for the development of enhanced therapeutic and vaccination strategies to exploit CD8+ T cell-mediated immunity.
Analysis of T cell repertoire defects in mice lacking immunoproteasome subunits
The immunoproteasome is a specialized complex which can be distinguished from the proteasome by the presence of three unique subunits, LMP2, LMP7, and MECL1, which are induced in the presence of IFN-γ. It typically generates peptides with optimal MHCI binding characteristics, and in this way, is thought to play a critical role in influencing epitope-specific CTL responses. However, transfer of immunoproteasome subunit knockout CD8+ T cells to wt mice (i.e. with normal epitope presentation), followed by influenza virus infection, revealed a direct influence of these subunits on the ability of naïve epitope-specific CD8+ T cell populations to respond following antigen challenge. These data suggest that the immunoproteasome subunits play direct and distinct roles in shaping the capacity of naïve T cells to respond to antigen challenge. It is likely that such effects are driven by changes in thymic epitope expression that influence the selection of antigen-specific T cell repertoires. However, direct effects of the immunoproteasome subunits on naïve CTLp frequencies or TCR repertoire diversity remain unknown. This project (undertaken in collaboration with Dr Weisan Chen from the Ludwig Institute for Cancer Research) involves the enumeration and TCR repertoire characterization of both naïve and immune influenza specific CTLps derived from immunoproteasome knockout mice, to determine the influence of these subunits on the generation of a normal T cell repertoire, and how perturbations in the naïve repertoire affect the subsequent immune response.
Research Staff
Ms Wan-Ting Kan (Research Assistant)
Ms Jing Guan (PhD student)
Recent Publications (2007 — present)
- Jenkins MR, La Gruta NL, Doherty PC, Trapani JA, Turner SJ, Waterhouse NJ. Visualizing CTL activity for different CD8+ effector T cells supports the idea that lower TCR/epitope avidity may be advantageous for target cell killing. Cell Death Differ 2009; 16(4): 537-42.
- La Gruta NL, Thomas PG, Webb AI, Dunstone MA, Cukalac T, Doherty PC, Purcell AW, Rossjohn J, Turner SJ. Epitope-specific TCR {beta} repertoire diversity imparts no functional advantage on the CD8+ T cell response to cognate viral peptides. Proc Natl Acad Sci USA 2008; 105(6): 2034-39.
- Lieu ZZ, Lock JG, Hammond LA, La Gruta NL, Stow JL, Gleeson PA. A trans-Golgi network golgin is required for the regulated secretion of TNF in activated macrophages in vivo. Proc Natl Acad Sci USA 2008; 105(9): 3351-56.
- 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(4): 2556-62.
- 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(6): 3818-22.
- Stambas J, Guillonneau C, Kedzierska K, Mintern JD, Doherty PC, La Gruta NL. Killer T cells in influenza. Pharmacol Ther 2008; 20(2): 186-96.
- Kedzierska K, La Gruta NL, Stambas J, Turner SJ, Doherty PC. Tracking phenotypically and functionally distinct T cell subsets via T cell repertoire diversity. Mol Immunol 2008; 45(3): 607-18.
- La Gruta NL, Kedzierska K, Stambas J, Doherty PC. A question of self-preservation: immunopathology in influenza virus infection. Immunol Cell Biol 2007; 85(2): 85-92.
- Denton AE, Doherty PC, Turner SJ*, La Gruta NL.* IL-18, but not IL-12, is required for optimal cytokine production by influenza virus-specific CD8+ T cells. Eur J Immunol 2007; 37(2): 368-75. [* denotes equivalent contributions]
- Young LJ, Wilson NS, Schnorrer P, Mount A, Lundie RJ, La Gruta NL, Crabb BS, Belz GT, Heath WR, Villadangos JA. Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens. Proc Natl Acad Sci USA 2007; 104(45): 17753-58.