Gebhardt laboratory: Adaptive immune responses to virus infections

• 
  Head of Laboratory
  Professor Thomas Gebhardt

  gebhardt@unimelb.edu.au

  +61 3 8344 6132

Research Overview

T cells mediate immune protection from infection with a broad range of microbes.  They exist as distinct subsets that have specialised functions during immune responses.  We wish to understand how these diverse T-cell functions are regulated within lymphoid and peripheral tissues during acute or renewed infection. Separately, we are interested in the generation and function of so-called memory T cells that emerge once infection has resolved.  Memory T cells are key to protection from reinfection and continuously patrol lymphoid and extralymphoid peripheral organs to facilitate early detection of invading pathogens (Figure 1).  We seek to understand how tissue-derived factors can "imprint" organ-specific immune surveillance and tissue retention by memory T cells.  In this regard, we have recently described that certain peripheral tissues can support the generation of a distinct subset of memory T cells now widely referred to as tissue-resident memory T cells (TRM).  TRM cells are sessile cells that permanently reside in tissues such as skin and mucosa.  They further differ from their circulating counterparts in the blood with regards to phenotype, transcriptional profile and protective function.  While TRM cells are now well characterised for the CD8 subset, it remains unclear whether similar populations of non-recirculating peripheral memory cells also exist in the CD4 T-cell subset.  Importantly, TRM cells provide immediate local immunity from renewed infection in barrier tissues lining the body's surfaces, which represent major portals of entry for various pathogens.  We are interested in understanding the generation and persistence of TRM cells in peripheral tissues (Figure 2) and in harnessing the protective potential of these cells with novel immunisation strategies. For the past five years, our research program has been funded by NHMRC project grants (APP628423, APP1003717, APP1059514 and APP1003717), as well as infrastructure and research support grants from the University of Melbourne.

Staff

Ms Emma Bawden, Research Officer
Dr David Freestone, Research Assistant
Dr Katharina Hochheiser, Research Officer
Mr Nathan McBain, Research Assistant
Mr Lewis Newland, PhD Graduate Researcher
Ms Teagan Wagner, Research Assistant

Funding

2018-2022 Peter MacCallum Cancer Centre Fellowship. T Gebhardt.

2019-2021 Cancer Council Victoria Grant. Tissue-resident memory T cells and melanoma-immune equilibrium. T Gebhardt.

2016-2020 Equity Trustees Grant. Infection control at body surfaces. T Gebhardt.

2017-2019 NHMRC Project Grants. Microbiota and T cell immunity. T Gebhardt and S Bedoui.

2016-2019 NHMRC Project Grant. CD4 memory T cell dynamics in peripheral tissues. T Gebhardt.

Research Publications

1. Carbone FR, Gebhardt T.
   Immunology. A neighborhood watch upholds local immune protection.
   Science 2014; 346: 40–41.
2. Macleod BL, Bedoui S, Hor JL, Mueller SN, Russell TA, Hollett NA, Heath WR, Tscharke DC, Brooks AG, Gebhardt T.
   Distinct APC subtypes drive spatially segregated helper versus killer T-cell effector activity during skin infection with HSV-1.
   PLoS Pathog 2014; 10: e1004303.
3. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, Vega-Ramos J, Lauzurica P, Mueller SN, Stefanovic T, Tscharke DC, Heath WR, Inouye M, Carbone FR, Gebhardt T.
   The development pathway for CD103+CD8+ tissue-resident memory T cells of skin.
   Nat Immunol 2013; 14: 1294–1301.
4. Gebhardt T, Mueller SN, Heath WR, Carbone FR.
   Peripheral tissue surveillance and residency by memory T cells.
   Trends Immunol 2013; 34: 27–32.
5. Gebhardt T, Mackay LM.
   Local immunity by tissue-resident CD8+ memory T cells.
   Front Immunol 2012; 3: 340.
6. Kupz A, Guarda G, Gebhardt T, Sander LE, Short KR, Diavatopoulos DA, Wijburg OL, Cao H, Waithman JC, Chen W, Fernandez-Ruiz D, Whitney PG, Heath WR, Curtiss R 3rd, Tschopp J, Strugnell RA, Bedoui S.
   NLRC4 inflammasomes in dendritic cell regulate noncognate effector function by memory CD8+ T cells.
   Nat Immunol 2012; 13: 162–169.
7. Mackay LK, Stock AT, Ma JZ, Jones CM, Kent SJ, Mueller SN, Heath WR, Carbone FR, Gebhardt T.
   Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation.
   Proc Natl Acad Sci USA 2012; 109: 7037-42.
8. Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, Carbone FR, Mueller SN.
   Different patterns of peripheral migration by memory CD4+ and CD8+ T cells.
   Nature 2011; 477: 216–219.
9. Gebhardt T, Wakim LM, Eidsmo LA, Reading PC, Heath WR, Carbone FR.
   Non-lymphoid tissue-resident memory T cells that provide enhanced local immunity in HSV infection.
   Nat Immunol 2009; 10: 524–530.
10. Gebhardt T, Carbone, FR.
    Immunology. A helper's guide to infection.
    Nature 2009; 462: 418–419.