The antigen presenting molecule MR1 binds riboflavin catabolites.

Major histocompatibility-complex (MHC) class I-related (MR1) protein presents vitamin B based antigens to Mucosal-Associated Invariant T (MAIT) cells. While microbial riboflavin precursors are well documented MR1 ligands, it is unclear whether host-generated riboflavin catabolites influence MR1-mediated immunity. Here, we report that riboflavin catabolites, including 10-formylmethylflavin (FMF), lumichrome, lumiflavin and alloxazine bind to MR1 with moderate affinity, while riboflavin itself binds weakly.

Antibody-like recognition of a γδ T cell receptor toward a foreign antigen.

The antigen recognition principles of B cells and αβ T cells have been well described compared to those of the γδ T cell. By way of their specificity conferring receptor (γδTCR), γδ T cells can directly bind proteinaceous antigens. A known γδ T cell and B cell model antigen is phycoerythrin (PE), a light harvesting protein from rhodophytes and cyanobacteria.

A molecular basis underpinning TRBV28 T-cell receptor recognition of MR1-antigen.

Mucosal-associated invariant T (MAIT) cells express a TRAV1-2 T-cell receptor (TCR) that recognizes microbial vitamin B2 derivatives presented by the major histocompatibility complex class I-related molecule (MR1). Most MAIT TCRs incorporate a biased TCR-β repertoire, predominantly TRBV20-1 and TRBV6, but some utilize other trbv genes, including TRBV28. A second conserved, albeit less frequent TRAV36 TRBV28 T-cell population exhibits MAIT-like phenotypic features but use a markedly distinct mode of MR1-antigen (Ag) recognition compared with MAIT TCR-MR1 binding.

An unconventional T cell nexus drives HCK-mediated chronic obstructive pulmonary disease in mice.

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory lung disease leading to progressive, destructive lung function decline, disability and death, and it is refractory to all current treatments. Haematopoietic cell kinase (HCK) is a druggable SRC-family non-receptor protein tyrosine kinase and COPD candidate gene. It is implicated in the chronic and non-resolving inflammation that causes mucosecretory bronchitis and destruction of small airways and alveoli, but how it drives pathophysiology remains obscure.

Direct recognition of an intact foreign protein by an αβ T cell receptor.

αβ T cell receptors (αβTCRs) co-recognise antigens when bound to Major Histocompatibility Complex (MHC) or MHC class I-like molecules. Additionally, some αβTCRs can bind non-MHC molecules, but how much intact antigen reactivities are achieved remains unknown. Here, we identify an αβ T cell clone that directly recognises the intact foreign protein, R-phycoerythrin (PE), a multimeric (αβ)γ protein complex.

Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers.

Butyrophilin (BTN) molecules are emerging as key regulators of T cell immunity; however, how they trigger cell-mediated responses is poorly understood. Here, the crystal structure of a gamma-delta T cell antigen receptor (γδTCR) in complex with BTN2A1 revealed that BTN2A1 engages the side of the γδTCR, leaving the apical TCR surface bioavailable. We reveal that a second γδTCR ligand co-engages γδTCR via binding to this accessible apical surface in a BTN3A1-dependent manner.

Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine.

Background: The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines.

Methods: We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain.

Corrigendum: Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2.

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CD1 and MR1: An update after a long-awaited reunion.

CD1 molecules and the MHC-related protein 1 (MR1) present lipid and small molecule antigens, respectively, for T cell surveillance. The biology of these molecules, the antigens they present, and the T cells that respond to them were recently discussed during the 12 International CD1-MR1 Meeting held in Gothenburg, Sweden.

Heterologous SARS-CoV-2 IgA neutralising antibody responses in convalescent plasma.

Objectives: Following infection with SARS-CoV-2, virus-specific antibodies are generated, which can both neutralise virions and clear infection via Fc effector functions. The importance of IgG antibodies for protection and control of SARS-CoV-2 has been extensively reported. By comparison, other antibody isotypes including IgA have been poorly characterised.

Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2.

The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus.

Intracellular radar: Understanding γδ T cell immune surveillance and implications for clinical strategies in oncology.

T cells play a key role in anticancer immunity, with responses mediated through a diversity of αβ or γδ T cell receptors. Although αβ and γδ T cells stem from common thymic precursors, the development and subsequent biological roles of these two subsets differ considerably. γδ T cells are an unconventional T cell subset, uniquely poised between the adaptive and innate immune systems, that possess the ability to recognize intracellular disturbances and non-peptide-based antigens to eliminate tumors.

Differential antigenic requirements by diverse MR1-restricted T cells.

MHC-related protein 1 (MR1) presents microbial riboflavin metabolites to mucosal-associated invariant T (MAIT) cells for surveillance of microbial presence. MAIT cells express a semi-invariant T-cell receptor (TCR), which recognizes MR1-antigen complexes in a pattern-recognition-like manner. Recently, diverse populations of MR1-restricted T cells have been described that exhibit broad recognition of tumor cells and appear to recognize MR1 in association with tumor-derived self-antigens, though the identity of these antigens remains unclear.

A point-of-care lateral flow assay for neutralising antibodies against SARS-CoV-2.

Background: As vaccines against SARS-CoV-2 are now being rolled out, a better understanding of immunity to the virus, whether from infection, or passive or active immunisation, and the durability of this protection is required. This will benefit from the ability to measure antibody-based protection to SARS-CoV-2, ideally with rapid turnaround and without the need for laboratory-based testing.

Methods: We have developed a lateral flow POC test that can measure levels of RBD-ACE2 neutralising antibody (NAb) from whole blood, with a result that can be determined by eye or quantitatively on a small instrument.

Recognition of the antigen-presenting molecule MR1 by a Vδ3 γδ T cell receptor.

Unlike conventional αβ T cells, γδ T cells typically recognize nonpeptide ligands independently of major histocompatibility complex (MHC) restriction. Accordingly, the γδ T cell receptor (TCR) can potentially recognize a wide array of ligands; however, few ligands have been described to date. While there is a growing appreciation of the molecular bases underpinning variable (V)δ1 and Vδ2 γδ TCR-mediated ligand recognition, the mode of Vδ3 TCR ligand engagement is unknown.

Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 variants via multiplex assay.

The SARS-CoV-2 receptor binding domain (RBD) is both the principal target of neutralizing antibodies and one of the most rapidly evolving domains, which can result in the emergence of immune escape mutations, limiting the effectiveness of vaccines and antibody therapeutics. To facilitate surveillance, we developed a rapid, high-throughput, multiplex assay able to assess the inhibitory response of antibodies to 24 RBD natural variants simultaneously. We demonstrate how this assay can be implemented as a rapid surrogate assay for functional cell-based serological methods to measure the SARS-CoV-2 neutralizing capacity of antibodies at the angiotensin-converting enzyme 2-RBD (ACE2-RBD) interface.

CD36 family members are TCR-independent ligands for CD1 antigen-presenting molecules.

CD1c presents lipid-based antigens to CD1c-restricted T cells, which are thought to be a major component of the human T cell pool. However, the study of CD1c-restricted T cells is hampered by the presence of an abundantly expressed, non-T cell receptor (TCR) ligand for CD1c on blood cells, confounding analysis of TCR-mediated CD1c tetramer staining. Here, we identified the CD36 family (CD36, SR-B1, and LIMP-2) as ligands for CD1c, CD1b, and CD1d proteins and showed that CD36 is the receptor responsible for non-TCR-mediated CD1c tetramer staining of blood cells.