Search

Despite extensive structural studies elucidating how antigens are anchored to antigen-presenting molecules and presented to T cells, little is known about the display mechanism of the lipid-antigen-presenting molecule CD1c. Here, by combining structural immunology, lipidomics, and biophysical analysis, the authors reveal that the CD1c binding cleft accommodates two different lipids, one of them with a bulky headgroup positioned sideways for display to T cells, rather than upwards, different from the conventional upright antigen-presentation mode

Rossjohn, van der Vliet and colleagues develop single-domain antibodies binding composite CD1d and NKT T-cell receptor antigens, inducing specific antitumor immune subsets.

Attachment of a piece of viral protein to a small RNA achieves transfer of the RNA into neuronal cells in cell culture. This was also able to deliver an antiviral siRNA specifically into the brains of mice infected with encephalitis and achieve 80% protection. This study opens a new potential line of treatment for neuronal disease.

How γδ TCRs bind antigen presented by antigen-presenting molecules remains unclear. Godfrey and colleagues describe a population of human γδ T cells that interacts with CD1d and provide a molecular basis for how a γδ TCR binds CD1d–α-GalCer.

Natural killer T (NKT) cells include type I that express semi-invariant T cell receptor (TCR), and type II that cover a broader repertoire. Here the authors describe the crystal structure of a type II NKT TCR complexed with CD1d/antigen to propose that type II NKT TCRs may adapt multiple CD1d docking modes to maximise antigen recognition efficacy.

Lynch, Brenner and colleagues find that tissue-resident γδ T cells reside in adipose tissues in both mice and humans. These cells play essential roles in regulating thermogenesis and supporting age-dependent increases in adipose-tissue regulatory T cell populations.

Type I natural killer T cells are characterized by an invariant V_α14-J_α18 T cell antigen receptor α-chain. Godfrey and colleagues describe a population of CD1d-restricted natural killer T cells that express a previously unidentified canonical V_α10-J_α50 α-chain.

Natural killer T cells (NKT cells) recognize lipid antigens presented by CD1d. Zajonc and Rossjohn and their colleagues describe molecular interactions between type II NKT cell antigen receptors and CD1d-ligand complexes, which demonstrate distinct modes of recognition used by the receptors.

Certain specific antigens have been shown to activate T cells in an MHC independent manner. Here the authors show a phycoerythrin reactive mouse TCR which recognises native protein and characterise the molecular nature of this interaction and that this specific TCR can be selected in the thymus.

In this study, Uldrich and colleagues describe the crystal structure of the Vγ9Vδ2 T cell antigen receptor (TCR) interacting with BTN2A1 and demonstrate the existence of a second ligand that co-binds to a distinct epitope on Vγ9Vδ2 TCR. Using these data, the authors suggest a model of Vγ9Vδ2 TCR activation in which BTN2A1 and BTN3A1 are tethered to each other at the steady state, and must disengage to allow TCR binding.

Mucosal-associated invariant T (MAIT) cells facilitate anti-microbial responses, but their functions in cancer protection is unclear. Here the authors show that activated MAIT cells induce an IFN-γ transcriptome in natural killer (NK) cells and enhance NK-dependent anti-cancer immunity in mice, thereby hinting a new avenue for cancer therapy.

Godfrey, Pellicci and colleagues define the developmental stages and checkpoints for the development of mucosal-associated invariant T cells in humans and mice.

The invariant αβTCR of type I NKT cells recognizes a lipid α-GalCer presented by CD1d. Here the authors describe atypical α-GalCer-reactive NKT cells with diverse TCRs, which bind to CD1d-α-GalCer in a manner distinct from type I NKT cells, thus unveiling greater diversity in lipid antigen recognition.

Analysis of 1.32 billion records of medication data from England, Scotland and Wales reveals that the COVID-19 pandemic led to substantial declines in dispensing of antihypertensive and lipid-lowering medications, leading to increased risks for future cardiovascular disease.

Here, the authors discuss how the T cell receptors expressed by natural killer T cells are able to recognize and respond to an array of self and foreign lipid antigens that are presented on CD1d molecules. They explain how a better understanding of these processes could be exploited for therapeutic purposes.

The immune response to SARS-CoV-2 infection is variable but has been linked to prognosis and the development of severe immunopathology. Here the authors assess a range of immune parameters in both peripheral blood and respiratory samples, providing a comparative assessment of the immune response between these compartments and their potential impact on immune-pathogenesis.

Several diseases are associated with reduced numbers of natural killer T (NKT) cells. The authors of this Review ask what drives NKT-cell development in the thymus and what factors ensure NKT-cell survival, maturation and function in the periphery?

CD1a presents a broad repertoire of lipid-based antigens. Rossjohn and colleagues show that the TCR docks over CD1a in a manner that precludes contact with permissive antigens, while nonpermissive antigens disrupt the TCR-CD1a contact.

Natural killer T cells (NKT cells) recognize lipid-based antigens presented by CD1d. The mammalian glycolipid β-glucosylceramide, a ubiquitous self antigen for NKT cells, is upregulated by microbial danger signals, which leads to activation of NKT cells in the absence of foreign glycolipid antigen.

Granulocyte colony-stimulating factor (G-CSF) is used to accelerate neutrophil engraftment in bone marrow transplant (BMT) recipients to reduce bacterial infections but may also enhance the risk of graft-versus-host disease (GVHD). Morris et al. now show that total body irradiation increases the expression of the G-CSF receptor on recipient dendritic cells, resulting in the activation of donor natural killer T cells and enhanced GVHD when G-CSF is administered shortly after BMT (pages 363–364).

Mucosal-associated invariant T (MAIT) cells express invariant TRAV1/TRAJ33 TCR-α gene segments and detect antigens presented by MR1. Here the authors show that atypical, MR1-restricted MAIT populations that include both Trav1⁺ and Trav1- cells are found in both Traj33-deficient mice and human peripheral blood.

Aspergillus fumigatus is a fungus that is associated with a severe form of asthma, although the precise immunological basis for this disease is unclear. A new study in mice shows that natural killer T (NKT) cells are crucial for progression of A. fumigatus–induced asthma and also identifies a glycolipid antigen from this fungus that seems to drive this NKT cell–mediated inflammatory response (pages 1297–1304).

Although the development of natural killer T cells is a T cell antigen receptor–dependent process, the signaling pathways involved are poorly defined. New data demonstrate that the calcineurin–transcription factor NFAT pathway exerts a critical influence on this process by controlling the transcription factor Egr2.

Here the authors use single cell profiling of T cells across the human lifespan to show that a suboptimal TCR shift in T cells as we enter older age results in a molecular signature that resembles that of T cells from newborns and children.

In contrast to microbial natural killer T cell ligands, self glycolipid antigens are β-linked. Rossjohn and co-workers provide the mechanism for the autoreactivity of natural killer T cell antigen receptors toward β-glycosylated agonists.

Mucosal-associated invariant T cells are evolutionarily conserved T lymphocytes with undefined antigen specificity. These cells are now shown to have a unique role in host defense by targeting highly conserved microbial antigens.

Whereas the adaptive immune response is essential for control and clearance of hepatitis B virus infection, the importance of the early innate immune response is controversial and the players involved are poorly defined. A new study shows that activation of natural killer T cells by infected hepatocytes is crucial for the early control of this disease (pages 1060–1068).

While most studies of T lymphocytes have focused on peptide-MHC-reactive T cells, many other types of T cells do not fit this paradigm. Here Godfrey et al. review the immunology of such unconventional T cells.

MAIT cells are abundant in the lungs and confer protection against bacterial pathogens. Whilst activation of these cells has been described during viral infections, here van Wilgenburg and colleagues show that in a murine model MAIT cells contribute to the protective host immune response to influenza virus infection.

iNKT cells in adipose tissue are anti-inflammatory. Brenner and colleagues show that adipose iNKT cells have a unique transcriptional program, produce IL-2 and IL-10 and lack expression of the transcription factor PLZF.

LUBAC is a ubiquitin ligase complex of HOIL-1, HOIP and SHARPIN important for signal transduction of a range of stimuli. Here the authors define the function of all three LUBAC components in T cell development and homeostasis.

The structure of the major histocompatibility complex (MHC)-class-I-like molecule MR1 in complex with a vitamin B9 derivative is determined; metabolites of vitamin B2 are shown to activate MR1-restricted mucosal-associated invariant T cells, implicating them in microbial immunosurveillance.

Dendritic cells classically require cognate licensing by helper T cells to cross-prime cytotoxic T cells. Kurts and colleagues have found an alternative mechanism of cognate licensing mediated by natural killer T cells.

To date, structural analysis has demonstrated a highly consistent binding pattern of the TCR to the MHC molecule. Rossjohn and colleagues reveal the first structures of two human T_reg cell TCRs and show that they bind with a reversed polarity to the MHC.

Mucosal associated invariant T (MAIT) cells have been implicated in antibacterial responses. Here the authors show MAIT cells confer IFN-γ-mediated protection from lethal infection in a mouse model of Legionella infection, which can be enhanced by synthetic MR1 ligands.

Whether natural killer T cells recognize antigens derived from dangerous pathogens remains unclear. New data demonstrate that a glycolipid from Borrelia burgdorferi, the causative agent of Lyme disease, directly stimulates mouse and human natural killer T cells.

Moody and colleagues identify a subset of T cells with high affinity for complexes of CD1b and mycobacterial glycolipids, conserved TCRα use and biased TCRβ use. These 'GEM' T cells show interdonor conservation and proliferate after infection.

Structural studies of CD1d presentation of α-galactosylceramide have shown that the lipid component fits snugly in the cleft, whereas the galactosyl head group protrudes upward, with key contact points between CD1d and the antigen conserved between mouse and human structures.