“Super” receptor that helps kill HIV infected cells.
Image: Vanette Tran
“We are using a technology to produce stable, antigen-specific MHC- class II tetramers that has permitted our team to track auto-reactive T cells relevant to disease.”
Within this theme, conceptual challenges lie in understanding how the T cell antigen receptor co-recognises peptide determinants while being presented by molecules encoded by the Major Histocompatibility Complex (MHC) – both in the context of protective immunity (e.g. to viruses) and aberrant immunity (eg autoimmunity). The Imaging CoE’s strategy is to develop reagents to characterise peptide-specific T-cells ex vivo and then use atomic and molecular imaging-based techniques to investigate the structural basis underpinning the interactions by the TCR.
PROF. JAIME ROSSJOHN
AT A GLANCE
This theme has continued a series of structural studies in the TCR-peptide-MHC axis central to protective and aberrant immunity, principally using protein chemistry and X-ray crystallography as the main experimental tools.
Concomitantly, we are using a technology to produce stable, antigen-specific MHC- class II tetramers that has permitted our team to track auto-reactive T cells relevant to disease.
This has led to:
- An increased understanding of the mechanisms of post-translational modifications of peptides and MHC presentation (JBC, Science Immunology and Proteomics).
- An understanding of how HLA polymorphism leads to protective immune responses in HIV elite controllers (Science Immunology).
- How TCRs can interact with tumour-derived epitopes via previously unknown mechanisms (Nature Communications). Collectively our work in the axis has led to some important basic insights into peptide-mediated immunity. Highlighting the standing of Imaging CoE investigators in the field, two authoritative reviews in MHC-restricted immunity were published in 2018. (Nature Reviews Immunology).
- Explore protective immune responses to lipid antigens.
- Examine CD1 auto reactivity in the context of health and autoimmunity.
A “super” receptor that helps kill HIV infected cells
While treatments for HIV mean that the disease is no longer largely fatal, the world still lacks a true therapy that can eradicate the virus across a globally – and genetically
different – population.
Imaging CoE researchers, together with colleagues from the Pasteur Institute in Paris, have discovered a unique set of “super” receptors on immune cells capable of killing HIV across genetically diverse populations, making them a potential candidate for immunotherapy treatments. The work was published in Science Immunology.
Professor Jamie Rossjohn, A/Professor Stephanie Gras from Monash University and ARC Centre of Advanced Molecular Imaging, and colleagues from the Pasteur Institute in Paris, studied fifteen unique individuals who all had been infected with HIV (ANRS CO21 CODEX cohort), but have immune systems that protect them from AIDs progression. These rare individuals, called HIV controllers, could hold clues to the cure for the disease.
Upon HIV infection, CD4 T cells, which are an important part of our protective immune system, can be depleted and drop dramatically in numbers, leading to a weak immune system with the progression of the disease to AIDs. These CD4 T cells can remain low even when the disease is kept in check with anti-retroviral therapy (ART), which is currently provided to more than half of people living with HIV globally. ART lowers the risk of mortality but does not eradicate the virus.
Rossjohn and his colleagues found that HIV controllers are able to retain CD4 T cells of a higher quality, able to detect and react to minute amounts of virus, therefore representing a great opportunity to study their potential role in HIV infection.
We discovered that those CD4 T cells, usually viewed as helper cells for the killer CD8 T cells that destroy infected cells, could be turned into killer cells themselves in HIV controllers. These killer CD4+ T cells could recognize very low amounts of HIV thanks to the expression of “super” T cell receptors on their surface. Importantly when they studied these receptors – they found identical receptors across multiple HIV controllers. “The likelihood of finding the exact same T cell receptor in different individuals is extremely low, like winning the lottery, and is likely linked to the control of HIV”, said Carine Farenc, a lead author of the study said.
T cell receptors recognises virus or bacteria fragments bound to specialised molecule called HLA (Human Leukocyte Antigen). HLA molecules are like fingerprints: every person has a specific combination of HLA molecules, which help the immune system recognize foreign invaders like bacteria or viruses. Monash University researchers used the Australian Synchrotron, effectively a giant microscope the size of a football field, to study the binding of this super T cell receptor in complex with the HIV antigen. This revealed another remarkable feature of those killer CD4 T cells: their ability to recognise HIV fragment in genetically diverse individuals (with different HLA molecules). The Gras team and her colleagues found that these killer CD4 T cells can bind with HLA molecules shared by a quarter of world population, a figure that is likely to increase as studies progress.
Image: Vanette Tran
Professor Jamie Rossjohn receives 2018 ASBMB Lemberg Medal
Professor Jamie Rossjohn was announced as the 2018 Australian Society for Biochemistry and Molecular Biology (ASBMB) Lemberg Medal recipient.
This prestigious medal honours Professor Rossjohn’s significant and sustained contributions to the understanding of the molecular basis underpinning immunity.
Awarded annually, the Lemberg medal is presented in memory of Emeritus Professor M.R. Lemberg, who was the Society’s first President and Honorary Member. Only three other scientists from Monash University have won this Medal. Professor Rossjohn joins the esteemed company of Professor Anthony Linnane (1973), Emeritus Professor Phillip Nagley (2001) and the Dean of the Faculty of Medicine, Nursing and Health Sciences and Academic Vice-President, Professor Christina Mitchell (2015).
“An outstanding team of researchers who work alongside me, coupled with the continuous and strong support of Monash University, have enabled numerous exciting finds in the area of immunity to be made over the last 15 years,” Professor Rossjohn said
Professor Rossjohn’s research on the immune system, how the body reacts to infection and what happens when the immune system fails has led to a sustained advancement of knowledge in the field of immunity. His work has been generously supported by the Anti-Cancer Council, the NHMRC, and the ARC, including the Imaging CoE.
As the recipient of the 2018 ASBMB Lemberg Medal, Professor Rossjohn also attended the ComBio2018 conference in September to give the Lemberg Medal Lecture.
Professor Jamie Rossjohn