WEHI immunologists seek to understand how the immune system develops and is regulated. The goal is to be able to guide the development of more effective vaccines and control or prevent autoimmunity (reactivity to self) and inflammatory responses. Milestone discoveries in immunology include:
Immunological recognition of self from non-self
Sir Macfarlane Burnet shared the 1960 Nobel Prize in Medicine or Physiology with Sir Peter Medawar for ‘acquired immunological tolerance’. Burnet’s proposal that the body’s tolerance to its own cells and tissues is acquired very early in life was demonstrated experimentally by Medawar and his colleagues. The physiological mechanisms conferring tolerance to self were greatly clarified by Sir Gustav Nossal.
- Burnet FM and Fenner F The production of Antibodies 2nd edn (Macmillan, London, 1949)
- FM Burnet Nobel lecture
- Nossal GJV and Pike BL (1975) Evidence for clonal abortion theory of B-lymphocyte tolerance J Exp Med 141(4) 904-17
- Nossal GJV and Pike BL (1980) Clonal anergy – Persistence in tolerant mice of antigen- binding lymphocytes-B incapable of responding to antigen or mitogen Proc Natl Acad Sci USA 77(3) 1602-06
- Nossal GJV (1983) Cellular mechanisms of immunological tolerance Ann Rev Immunol 1 33- 62
- Nossal GJV (1994) Negative selection of lymphocytes Cell 76(2) 229-239
Clonal selection theory of antibody production
Burnet sought to explain how the body can make such an immense repertoire of antibodies to protect us against infectious agents. He proposed that the immune system generates a very large number of different lymphocytes, each capable of interacting with a different foreign entity (antigen), and that when a particular lymphocyte encounters a ‘matching’ foreign antigen it is stimulated to produce many clones of itself to fight the infection. The central tenet of this clonal selection theory, that a single lymphocyte makes only a single type of antibody, was established experimentally by Nossal.
- Burnet FM (1959) A modification of Jerne’s theory of antibody production using the concept of clonal selection Aust J Science 20 67-69
- See also Hodgkin PD, Heath WR, and Baxter AG (2007) The clonal selection theory: 50 years since the revolution Nat Immunol 8:1019-1026
- Nossal GJV and Lederberg J (1958) Antibody production by single cells Nature 181 1419-1420
T-B cell collaboration
Following his momentous discovery (in London) of the essential role of the thymus in the immune system, Jacques Miller, together with his student Graham Mitchell, discovered that T lymphocytes derived from the thymus 'helped' B lymphocytes accomplish their task of making antibodies.
- Miller JF and Mitchell GF (1968) Cell to cell interaction in the immune response I Hemolysin-forming cells in neonatally thymectomized mice reconstituted with thymus or thoracic duct lymphocytes J Exp Med 1968 128(4) 801-20
- Mitchell GF and Miller JFAP (1968) Cell to cell interaction in the immune response II The source of hemolysin-forming cells in irradiated mice given bone marrow and thymus or thoracic duct lymphocytes J Exp Med 128 821-837 PMID: 5691986
Identification of the earliest T cell and dendritic cell precursor in the thymus
A rare cell in the thymus was shown to be able to generate both T lymphocytes and dendritic cells, which are remarkable cells tasked with processing foreign proteins into pieces (antigens) for presentation on their surface to other cells of the immune system.
- Wu L, Scollay R Egerton M Pearse M Spangrude GJ and Shortman K (1991) CD4 expressed on earliest T-lineage precursor cells in the adult murine thymus Nature 349 71-4 PMID: 1702186
- Ardavin C, Wu L, Li CL and Shortman K (1993) Thymic dendritic cells and T cells develop simultaneously from a common precursor population Nature 362(6422) 761-3 PMID: 8469288
Dendritic cell subtypes and their specialised roles in immune responses
Dendritic cells are master controllers of immunity. They have been found in many different locations in the body and there are a surprising diversity of subtypes, with specialised roles. Follicular dendritic cells are crucial to inducing good quality antibodies.
- Nossal GJV and Ada GL (1971) Antigens, Lymphoid Cells and the Immune Response Academic Press, New York and London
- Shortman K and Liu Y-J (2002) Mouse and human dendritic cell subtypes Nat.Rev.Immunol. 2:151-161.
- Belz GT, Behrens GM, Smith CM, Miller JF, Jones C, Lejon K, Fathman CG, Mueller SN, Shortman K, Carbone FR and Heath WR (2002) The CD8a+ dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens. J Exp Med 196:1099-1104.
- Schnorrer P, Behrens GMN, Wilson NS, Pooley JL, Smith CM, El-Sukkari D, Davey G, Kupresanin F, Lee M, Maraskovsky E, Belz GT, Carbone FR, Shortman K, Heath WR and Villadangos JA (2006) The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture Proc.Nat.Acad.Sci.USA 103:10729:10734.
- Proietto AI, vanDommelen S, Zhou P, Rizzzitelli A, D'Amico A, Steptoe RJ, Naik SH, Lahoud MH, Liu Y, Zheng P, Shortman K and Wu L. (2008) Dendritic cells in the thymus contribute to T-regulatory cell induction Proc.Nat.Acad.Sci.USA. 105:19869-19874.
Targeting antigen-presenting cells to enhance induction of immune responses
A novel approach offering the prospect of improving vaccine efficacy.
- Boyle JS, Brady JL and Lew AM (1998) Enhanced responses to a DNA vaccine encoding a fusion antigen that is directed to sites of immune induction Nature 392:408-11