ORCID Profile
0000-0003-1205-683X
Current Organisation
University of Melbourne
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Infectious Agents | Cellular Immunology | Immunology | Cell Development, Proliferation and Death
Immune System and Allergy | Expanding Knowledge in the Medical and Health Sciences |
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-2019
DOI: 10.1126/SCIIMMUNOL.AAW0402
Abstract: ICOS- and IL-23–mediated costimulation are important for driving in vivo activation of antigen-specific MAIT cells.
Publisher: Springer Science and Business Media LLC
Date: 09-11-2018
DOI: 10.1038/S41467-018-07207-9
Abstract: Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo. Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulate and are activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post-infection. Activation is modulated via cytokines independently of MR1. MAIT cell-deficient MR1 −/− mice show enhanced weight loss and mortality to severe (H1N1) influenza. This is ameliorated by prior adoptive transfer of pulmonary MAIT cells in both immunocompetent and immunodeficient RAG2 −/− γC −/− mice. Thus, MAIT cells contribute to protection during respiratory viral infections, and constitute a potential target for therapeutic manipulation.
Publisher: Research Square Platform LLC
Date: 30-06-2021
DOI: 10.21203/RS.3.RS-612599/V1
Abstract: Mucosal-associated invariant T (MAIT)-cells are restricted by MR1 and are known to contribute to protection from bacterial and viral infections. Here we show that MAIT-cells also play an important role in protection from visceral leishmaniasis-VL, caused by protozoan parasites of the Leishmania donovani complex. In response to L. infantum, human peripheral blood MAIT-cells produced TNF and IFN-γ and this was MR1-dependent. Since Leishmania spp. lack riboflavin biosynthesis, this suggests that novel MAIT-cell antigen(s) exist in the context of Leishmania-infection. In asymptomatic in iduals, MAIT-cells also produced IL-17A, dependent on MR1, a cytokine signature associated with resistance to visceral Leishmaniasis. In mice, MAIT-cells reduced parasite burden during peak infection and decreased pathology. In summary, these results broaden our understanding of MAIT-cell immunity to include protection from parasitic infections with implications for MAIT-cell based therapeutics and vaccines. Leishmania is an ancient and clinically important pathogen such that it may have contributed to shaping MAIT-cell biology.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2023
Publisher: Springer Science and Business Media LLC
Date: 23-12-2020
DOI: 10.1038/S41594-019-0353-4
Abstract: The human leukocyte antigen (HLA) locus is strongly associated with T cell-mediated autoimmune disorders. HLA-DQ2.5-mediated celiac disease (CeD) is triggered by the ingestion of gluten, although the relative roles of genetic and environmental risk factors in CeD is unclear. Here we identify microbially derived mimics of gliadin epitopes and a parental bacterial protein that is naturally processed by antigen-presenting cells and activated gliadin reactive HLA-DQ2.5-restricted T cells derived from CeD patients. Crystal structures of T cell receptors in complex with HLA-DQ2.5 bound to two distinct bacterial peptides demonstrate that molecular mimicry underpins cross-reactivity toward the gliadin epitopes. Accordingly, gliadin reactive T cells involved in CeD pathogenesis cross-react with ubiquitous bacterial peptides, thereby suggesting microbial exposure as a potential environmental factor in CeD.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-09-2019
Abstract: Antibodies to the M protein and SpeC resolve streptococcal toxic shock syndrome in HLA-humanized mice.
Publisher: Rockefeller University Press
Date: 26-08-2022
DOI: 10.1084/JEM.20210828
Abstract: Mucosal-associated invariant T (MAIT) cells detect microbial infection via recognition of riboflavin-based antigens presented by the major histocompatibility complex class I (MHC-I)–related protein 1 (MR1). Most MAIT cells in human peripheral blood express CD8αα or CD8αβ coreceptors, and the binding site for CD8 on MHC-I molecules is relatively conserved in MR1. Yet, there is no direct evidence of CD8 interacting with MR1 or the functional consequences thereof. Similarly, the role of CD8αα in lymphocyte function remains ill-defined. Here, using newly developed MR1 tetramers, mutated at the CD8 binding site, and by determining the crystal structure of MR1–CD8αα, we show that CD8 engaged MR1, analogous to how it engages MHC-I molecules. CD8αα and CD8αβ enhanced MR1 binding and cytokine production by MAIT cells. Moreover, the CD8–MR1 interaction was critical for the recognition of folate-derived antigens by other MR1-reactive T cells. Together, our findings suggest that both CD8αα and CD8αβ act as functional coreceptors for MAIT and other MR1-reactive T cells.
Publisher: Wiley
Date: 13-04-2020
DOI: 10.1111/ALL.14279
Abstract: Conventional T cells recognise protein‐derived antigens in the context of major histocompatibility complex (MHC) class Ia and class II molecules and provide anti‐microbial and anti‐tumour immunity. Conventional T cells have also been implicated in type IV (also termed delayed‐type or T cell–mediated) hypersensitivity reactions in response to protein‐derived allergen antigens. In addition to conventional T cells, subsets of unconventional T cells exist, which recognise non‐protein antigens in the context of monomorphic MHC class I‐like molecules. These include T cells that are restricted to the cluster of differentiation 1 (CD1) family members, known as CD1‐restricted T cells, and mucosal‐associated invariant T cells (MAIT cells) that are restricted to the MHC‐related protein 1 (MR1). Compared with conventional T cells, much less is known about the immune functions of unconventional T cells and their role in hypersensitivities. Here, we review allergen antigen presentation by MHC‐I‐like molecules, their recognition by unconventional T cells, and the potential role of unconventional T cells in hypersensitivities. We also speculate on possible scenarios of allergen antigen presentation by MHC‐I‐like molecules to unconventional T cells, the hallmarks of such responses, and the expected frequencies of hypersensitivities within the human population.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-2019
DOI: 10.1126/SCIIMMUNOL.AAY6039
Abstract: Characterizing MAIT cell development led to the identification of key regulators that specify MAIT cell fate in the thymus.
Publisher: Research Square Platform LLC
Date: 15-07-2020
DOI: 10.21203/RS.3.RS-39302/V1
Abstract: Mucosal-Associated Invariant T (MAIT) cells have potent antibacterial functions. Their protective capacity, in vivo, has been demonstrated in mouse models, particularly of respiratory infections. We now show that during systemic infection of mice with Francisella tularensis Live Vaccine Strain (LVS), MAIT cell expansion was evident in the liver, lungs, kidney, spleen and blood. MAIT cells manifested a polarised Th1-like (termed “MAIT-1”) phenotype and cytokine profile that conferred a critical role in controlling bacterial load. After resolution of the primary infection, the expanded MAIT cells developed to a stable memory-like MAIT-1 cell population, suggesting a basis for vaccination and protection against subsequent challenge. Indeed, a systemic vaccination with synthetic ligand (5-OP-RU) in combination with CpG adjuvant boosted MAIT-1 cells and resulted in enhanced protection against systemic and local infections with F. tularensis and Legionella longbeachae. Our study highlights the potential utility of targeting MAIT cells to combat multiple bacterial pathogens.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2021
DOI: 10.1038/S41467-021-24570-2
Abstract: Mucosal-associated Invariant T (MAIT) cells are recognized for their antibacterial functions. The protective capacity of MAIT cells has been demonstrated in murine models of local infection, including in the lungs. Here we show that during systemic infection of mice with Francisella tularensis live vaccine strain results in evident MAIT cell expansion in the liver, lungs, kidney and spleen and peripheral blood. The responding MAIT cells manifest a polarised Th1-like MAIT-1 phenotype, including transcription factor and cytokine profile, and confer a critical role in controlling bacterial load. Post resolution of the primary infection, the expanded MAIT cells form stable memory-like MAIT-1 cell populations, suggesting a basis for vaccination. Indeed, a systemic vaccination with synthetic antigen 5-(2-oxopropylideneamino)-6- d -ribitylaminouracil in combination with CpG adjuvant similarly boosts MAIT cells, and results in enhanced protection against both systemic and local infections with different bacteria. Our study highlights the potential utility of targeting MAIT cells to combat a range of bacterial pathogens.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-02-2019
DOI: 10.1126/SCIIMMUNOL.AAL2201
Abstract: Quantitative activity through the TCR-proximal protein network specifies thymic positive versus negative selection.
Publisher: Springer Science and Business Media LLC
Date: 21-05-2019
DOI: 10.1038/S41467-019-10198-W
Abstract: Mucosal-associated invariant T (MAIT) cells express an invariant TRAV1/TRAJ33 TCR-α chain and are restricted to the MHC-I-like molecule, MR1. Whether MAIT cell development depends on this invariant TCR-α chain is unclear. Here we generate Traj33 -deficient mice and show that they are highly depleted of MAIT cells however, a residual population remains and can respond to exogenous antigen in vitro or pulmonary Legionella challenge in vivo. These residual cells include some that express Trav1 + TCRs with conservative Traj -gene substitutions, and others that express Trav1 - TCRs with a broad range of Traj genes. We further report that human TRAV1-2 - MR1-restricted T cells contain both MAIT-like and non-MAIT-like cells, as judged by their TCR repertoire, antigen reactivity and phenotypic features. These include a MAIT-like population that expresses a public, canonical TRAV36 + TRBV28 + TCR. Our findings highlight the TCR ersity and the resulting potential impact on antigen recognition by MR1-restricted T cells.
Publisher: Springer Science and Business Media LLC
Date: 19-03-2021
DOI: 10.1038/S41467-021-22036-Z
Abstract: T-cell immunity is important for recovery from COVID-19 and provides heightened immunity for re-infection. However, little is known about the SARS-CoV-2-specific T-cell immunity in virus-exposed in iduals. Here we report virus-specific CD4 + and CD8 + T-cell memory in recovered COVID-19 patients and close contacts. We also demonstrate the size and quality of the memory T-cell pool of COVID-19 patients are larger and better than those of close contacts. However, the proliferation capacity, size and quality of T-cell responses in close contacts are readily distinguishable from healthy donors, suggesting close contacts are able to gain T-cell immunity against SARS-CoV-2 despite lacking a detectable infection. Additionally, asymptomatic and symptomatic COVID-19 patients contain similar levels of SARS-CoV-2-specific T-cell memory. Overall, this study demonstrates the versatility and potential of memory T cells from COVID-19 patients and close contacts, which may be important for host protection.
Location: China
Location: China
Start Date: 2021
End Date: 12-2023
Amount: $434,588.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2017
End Date: 2019
Funder: National Health and Medical Research Council
View Funded Activity