Chancellery Research - Research Publications
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ItemThe establishment of a cytomegalovirus -specific CD8+ T-cell threshold by kinetic modeling for the prediction of post-hemopoietic stem cell transplant reactivation(CELL PRESS, 2022-11-18)The dynamic interaction between the CMV virus and host immune response remains obscure, thus hindering the diagnosis and therapeutic management of patients with HSCT. The current diagnosis of CMV viremia depends on viral load estimation. Medical intervention based on viral load, can be unnecessary or poorly timed for many patients. Here we examined the clinical features and blood samples of patients with HSCT and assessed the CMV reactivation kinetics and corresponding CMV antigen-specific T-cell response in individual patients based on a peptide pool stimulation T-cell assay, which showed that CMV-specific CD8+ T cells were more suitable to be a diagnosis indicator for suppressing CMV reactivation. Using ROC analysis, we defined and verified a CMV-specific CD8+ T-cell counts threshold (925 cells/106 PBMCs) as an indicator of CMV reactivation post-HSCT, and suggested that use of this threshold would provide more accurate guidance for prompt medication and better management of CMV infection post-HSCT.
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ItemCD8 coreceptor engagement of MR1 enhances antigen responsiveness by human MAIT and other MR1-reactive T cells(Rockefeller University Press, 2022)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.
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ItemNo Preview AvailableThe balance of interleukin-12 and interleukin-23 determines the bias of MAIT1 versus MAIT17 responses during bacterial infection(WILEY, 2022-08)Mucosal-associated invariant T (MAIT) cells are a major subset of innate-like T cells mediating protection against bacterial infection through recognition of microbial metabolites derived from riboflavin biosynthesis. Mouse MAIT cells egress from the thymus as two main subpopulations with distinct functions, namely, T-bet-expressing MAIT1 and RORγt-expressing MAIT17 cells. Previously, we reported that inducible T-cell costimulator and interleukin (IL)-23 provide essential signals for optimal MHC-related protein 1 (MR1)-dependent activation and expansion of MAIT17 cells in vivo. Here, in a model of tularemia, in which MAIT1 responses predominate, we demonstrate that IL-12 and IL-23 promote MAIT1 cell expansion during acute infection and that IL-12 is indispensable for MAIT1 phenotype and function. Furthermore, we showed that the bias toward MAIT1 or MAIT17 responses we observed during different bacterial infections was determined and modulated by the balance between IL-12 and IL-23 and that these responses could be recapitulated by cytokine coadministration with antigen. Our results indicate a potential for tailored immunotherapeutic interventions via MAIT cell manipulation.
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ItemNo Preview AvailableMouse models illuminate MAIT cell biology(PERGAMON-ELSEVIER SCIENCE LTD, 2021-02)The field of mucosal-associated invariant T cell (MAIT) biology has grown rapidly since the identification of the vitamin-B-based antigens recognised by these specialised T cells. Over the past few years, our understanding of the complexities of MAIT cell function has developed, as they find their place among the other better known cells of the immune system. Key questions relate to understanding when MAIT cells help, when they hinder or cause harm, and when they do not matter. Exploiting mouse strains that differ in MAIT cell numbers, leveraged by specific detection of MAIT cells using MR1-tetramers, it has now been shown that MAIT cells play important immune roles in settings that include bacterial and viral infections, autoimmune diseases and cancer. We have also learnt much about their development, modes of activation and response to commensal microbiota, and begun to try ways to manipulate MAIT cells to improve disease outcomes. Here we review recent studies that have assessed MAIT cells in models of disease.
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ItemFrancisella tularensis induces Th1 like MAIT cells conferring protection against systemic and local infection(NATURE PORTFOLIO, 2021-07-16)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.
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ItemIL-17 production by tissue-resident MAIT cells is locally induced in children with pneumonia(ELSEVIER SCIENCE INC, 2020-09)Community-acquired pneumonia (CAP) contributes substantially to morbidity and mortality in children under the age of 5 years. In examining bronchoalveolar lavages (BALs) of children with CAP, we found that interleukin-17 (IL-17) production was significantly increased in severe CAP. Immune profiling showed that mucosal-associated invariant T (MAIT) cells from the BALs, but not blood, of CAP patients actively produced IL-17 (MAIT17). Single-cell RNA-sequencing revealed that MAIT17 resided in a BAL-resident PLZFhiCD103+ MAIT subset with high expression of hypoxia-inducible factor 1α (HIF-1α), reflecting the hypoxic state of the inflamed tissue. CAP BALs also contained a T-bet+ MAIT1 subset and a novel DDIT3+ (DNA damage-inducible transcript 3-positive) MAIT subset with low expression of HIF1A. Furthermore, MAIT17 differed from T-helper type 17 (Th17) cells in the expression of genes related to tissue location, innateness, and cytotoxicity. Finally, we showed that BAL monocytes were hyper-inflammatory and elicited differentiation of MAIT17. Thus, tissue-resident MAIT17 cells are induced at the infected respiratory mucosa, likely influenced by inflammatory monocytes, and contribute to IL-17-mediated inflammation during CAP.