Faculty of Medicine, Dentistry and Health Sciences Department of Microbiology and Immunology

Heath Laboratory

Find an Expert - Heath

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Include: Research Interests | Major Research Projects | Laboratory Staff | Recent Publications

Research Interests

Peripheral Tolerance

Killer (or CD8+) T cells are critically important in protecting us against viral infection and tumour development. However, occasionally killer T cells are inappropriately activated and attack the body’s own tissues and cause autoimmune diseases, such as type I diabetes. Nevertheless, the majority of us fail to develop autoimmunity despite the presence of cells capable of causing autoimmune disease within our circulation. We are interested in understanding how these circulating autoreactive T cells are controlled in healthy individuals. Through the use of mouse models, we are characterising the molecular and cellular components that regulate the activation of killer T cells and normally prevent them from being inappropriately triggered to cause autoimmunity.

AIRE

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disorder caused by loss of function mutations in the autoimmune regulator (AIRE) gene. APECED is the only organ-specific human autoimmune disease described that affects multiple organs, targeting both endocrine and non-endocrine tissues. The AIRE gene encodes a transcription factor that promotes the ‘promiscuous’ expression of tissue-specific antigens in the thymic medulla. This intrathymic expression of tissue-specific antigens is associated with negative selection of autoreactive T cells to establish of self tolerance. Using mouse models, we are characterising the cellular and molecular components involved in AIRE-dependent negative selection to gain further insight into the development of autoimmunity.

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SOCS1

Suppressor of Cytokine Signalling-1 (SOCS1) is a cytoplasmic protein involved in the negative regulation of JAK-STAT cytokine signalling pathways. We have shown that SOCS1 deficient CD8 T cells have an activated phenotype and undergo dysregulated homeostatic proliferation that is dependent on a TCR signal and the cytokine IL-15. We are interested in identifying the cytokines that drive this dysregulated response, with the aim of defining those checkpoints normally regulated by SOCS1 in wild-type T cells. Our interests also lie in dissecting the cellular interactions that are important for the development of autoimmunity in the absence of SOCS1.

Viral Immunity

The precise mechanisms responsible for the initiation and magnitude of primary T cell responses following viral infections still remain largely unclear. We have recently demonstrated that priming of virus-specific CD8 T cells is highly depend on the interaction of dendritic cells migrating to the lymph node from the site of infection and a lymph node-resident dendritic cell, identified by expression of CD8. Currently, we are investigating the molecular basis for the cross-talk between these different types of dendritic cells and their role in presenting antigen to virus-specific CD4 T cells.

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Malaria Immunity

Infection with malaria-causing Plasmodium parasites can induce immunity, immunopathology and immunosuppression, all of which interplay to impact on different disease outcomes ranging from asymptomatic infection through to lethal malaria. The priming of cellular responses to Plasmodium is presumably crucial to these different outcomes, but is poorly understood, at least in part due to a lack of tools to dissect malaria-specific cellular immunity. Our approach has been to combine recent advances in rodent malaria transfection technology with the latest tools available in dendritic cell and T cell biology to investigate the complex mechanisms that give rise to immunity and pathology during blood-stage malaria infection.

Major Research Projects

  1. Peripheral tolerance to model self antigens
  2. Cross-priming in viral immunity
  3. Defining the mechanistic basis for cross-presentation
  4. Examining immunity to blood-stage infections in murine malaria
  5. The role of SOCS1 in controlling CD8+ T cell responses
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Laboratory Staff

Professor William (Bill) Heath

Email: wrheath@unimelb.edu.au

Dr Gayle Davey (SRO)
Dr Scott Mueller (SRO)
Dr Sammy Bedoui (SRO)
Dr Catherine van Vliet (RO)
Dr Daniel Fernandez Ruiz (RO)
Lei Shong Lau (PhD Student)
Brooke Davies (research assistant)
JoAnn Kellan (research assistant)

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RECENT PUBLICATIONS

List of Publications prior to 2007

  1. Campbell IK, Kinkel S, Drake SF, van Nieuwenhuijze A, Hubert F, Tarlinton DM, Heath W, Scott HS, Wicks IP. Autoimmune regulator controls T cell help for pathogenetic autoanitbody production in collagen-induced arthritis. Arthritis and Rheumatism 2009; 60: 1683-1693.
  2. Bedoui S, Prato S, Mintern J, Gebhardt T, Zhan Y, Lew AM, Heath W, Villadangos JA, Segura E. Characterization of an immediate splenic precursor of CD8+ dendritic cells capable of inducing antiviral T cell responses. Journal of Immunology 2009; 182: 4200-4207.
  3. Bedoui S, Whitney P, Waithman J, Eidsmo L, Wakim L, Caminschi I, Allan R, Wojtasiak M, Shortman K, Carbone R, Brooks A, Heath W. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nature Immunology 2009; 10: 488-495.
  4. Eidsmo L, Allan R, Caminschi I, van Rooijen N, Heath W, Carbone F. Differential migration of epidermal and dermal dendritic cells during skin infection. Journal of Immunology 2009; 182: 3165-3172.
  5. Bedoui S, Davey G, Lew A, Heath W. Equivalent stimulation of naive and memory CD8 T cells by DNA vaccination: a dendritic cell-dependent process. Immunology and Cell Biology 2009; 87: 255-259.
  6. Nie C, Bernard N, Norman M, Amante F, Lundie R, Crabb B, Heath W, Engwerda C, Hickey M, Hansen D, Schofield L. IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection. PLoS Pathogens 2009; 5: 1-16.
  7. Gebhardt T, Wakim L, Eidsmo L, Reading P, Heath W, Carbone F. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nature Immunology 2009; 10: 524-530.
  8. Johnson S, Zhan Y, Sutherland RM, Mount A, Bedoui S, Brady JL, Carrington EM, Brown L, Belz GT, Heath W, Lew AM. Selected toll-like receptor ligands and viruses promote helper-independent cytotoxic T cell priming by upregulating CD40L on dendritic cells. Immunity 2009; 30: 218-227.
  9. Lahoud MH, Proeitto AI, Ahmet F, Kitsoulis S, Eidsmo L, Wu L, Sathe P, Pietersz S, Chang H, Walker ID, Maraskovsky E, Braley H, Lew AM, Wright MD, Heath W, Shortman K, Caminschi I. The C-type lectin Clec12A present on mouse and human dendritic cells can serve as a target for antigen delivery and enhancement of antibody responses. Journal of Immunology 2009; 182: 7587-7594.
  10. Parish IA, Rao S, Smyth GK, Juelich T, Denyer GS, Davey G, Strasser A, Heath W. The Molecular signature of CD8+ T cells undergoing deletional tolerance. Blood 2009; 118: 4575-4585.
  11. Parish IA, Waithman J, Davey GM, Belz GT, Mintern J, Kurts C, Sutherland RM, Carbone F, Heath W. Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance. Proc Nat Acad Sci (USA) 2009; 106: 3901-3906.
  12. Hubert FX, Kinkel SA, Webster KE, Cannon P, Crewther PE, Proeitto AI, Wu L, Heath WR, Scott HS. A specific anti-Aire antibody reveals aire expression is restricted to medullary thymic epithelial cells and not expressed in periphery. J Immunol. 2008 Mar 15;180(6): 3824-32.
  13. Wakim L, Gebhardt T, Heath W, Carbone F. Cutting edge: Local recall responses by memory T cells newly recruited to peripheral nonlymphoid tissues. Journal of Immunology 2008; 181: 5837-5841.
  14. Young L, Wilson N, Schnorrer P, Proietto A, Broeke T, Matsuki Y, Mount A, Belz G, O'Keefe M, Ohmura-Hoshino M, Ishido S, Stoorvogel W, Heath W, Shortman K, Villadangos J. Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells. Nature Immunology 2008; 9: 1244-52.
  15. White P, Anastasopoulos F, Church J, Kuo C-Y, Boyd B, Hickey P, Sze Tu L, Burns P, Lew A, Heath W, Davey H, Pouton C. Generic construction of single component particles that elicit humoural and cellular immune responses without the need for adjuvants. Vaccine 2008; 26: 6824-6831.
  16. Mount AM, Smith CM, Kupresanin F, Stoermer K, Heath W, Belz GT. Multiple dendritic cell populations activate CD4+ T cells after viral stimulation. PLoS One 2008; 3: e1691.
  17. Wilson NS, Young LJ, Kupresanin F, Naik SH, Vremec D, Heath W, Akira S, Shortman K, Boyle J, Maraskovsky E, Belz GT, Villadangos JA. Normal proportion and expression of maturation markers in migratory dendritic cells in the absence of germs or Toll-like receptor signaling. Immunology and Cell Biology 2008; 86: 200-205.
  18. Lin ML, Zhan Y, Proeitto AI, Prato S, Wu L, Heath W, Villadangos JA, Lew AM. Selective suicide of cross-presenting CD8+ dendritic cells by cytochrome c injection shows functional heterogeneity within this subset. Proc Nat Acad Sci (USA) 2008; 105: 3029-3034.
  19. Caminschi I, Proietto AI, Ahmet F, Kitsoulis S, Shin Teh J, Lo J, Rizzitelli A, Wu L, Vremec D, van Dommelen S, Campbell I, Maraskovsky E, Braley H, Davey G, Mottram P, van de Velde N, Jensen K, Lew A, Wright M, Heath W, Shortman K, Lahoud M. The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement. Blood 2008; 112: 3264-73.
  20. Parish IA, Heath WR. Too dangerous to ignore: self-tolerance and the control of ignorant autoreactive T cells. Immunol Cell Biol. 2008 Feb;86(2): 146-52. Epub 2008 Jan 29. Review.
  21. Caminschi I, Ahmet F, Heger K, Brady J, Nutt SL, Vremec D, Pietersz S, Lahoud MH, Schofield L, Hansen DS, O'Keeffe M, Smyth MJ, Bedoui S, Davey GM, Villadangos JA, Heath W, Shortman K. Putative IKDCs are functionally and developmentally similar to natural killer cells, but not to dendritic cells. Journal of Experimental Medicine 2007; 204: 2579-2590.
  22. Hodgkin PD, Heath W, Baxter AG. The Clonal selection theory: 50 years since the revolution. Nature Immunology 2007; 8: 1019-1026.
  23. Waithman J, Allan RS, Kosaka H, Azukizawa H, Shortman K, Lutz MB, Heath WR, Carbone FR, Belz GT. Skin-derived dendritic cells can mediate deletional tolerance of class I-restricted self-reactive T cells. J Immunol 2007 Oct 1;179(7): 4535-41.
  24. Belz GT, Bedoui S, Kupresanin F, Carbone FR, Heath WR. Minimal activation of memory CD8+ T cell by tissue-derived dendritic cells favors the stimulation of naive CD8+ T cells. Nat Immunol 2007 Oct;8(10): 1060-6. Epub 2007 Sep 2.

 

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