Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d

Almeida, Catarina; Smith, D.M.; Cheng, Tan-Yun; Harpur, Christopher M.; Batleska, Elena; Nguyen-Robertson, Catriona V.; Nguyen, Tram Anh Thi; Thelemann, Tamara; Reddiex, Scott J. J.; Li, Shihan; Eckle, Sidonia B G; Rhijn, Ildiko Van; Rossjohn, Jamie; Uldrich, Adam P.; Moody, D. Branch; Williams, Spencer J.; Pellicci, Daniel G.; Godfrey, Dale I.

doi:10.1073/pnas.2104420118

Cited by 13 publications

(16 citation statements)

References 60 publications

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“…Moreover, two of the TCR alpha clonotypes therein described fit the CAIT CDR3 motif (figure 1B). 19 36 Given these results, we hypothesise that CAIT cells may be reactive to CD1d and thus be a semi-invariant subgroup of the NKT type II family. Indeed, identification of HLA and antigen specificity is an essential step in T cell characterisation.…”

Section: Discussionmentioning

confidence: 89%

A novel unconventional T cell population enriched in Crohn’s disease

Rosati

Martini

Pogorelyy

et al. 2022

Gut

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ObjectiveOne of the current hypotheses to explain the proinflammatory immune response in IBD is a dysregulated T cell reaction to yet unknown intestinal antigens. As such, it may be possible to identify disease-associated T cell clonotypes by analysing the peripheral and intestinal T-cell receptor (TCR) repertoire of patients with IBD and controls.DesignWe performed bulk TCR repertoire profiling of both the TCR alpha and beta chains using high-throughput sequencing in peripheral blood samples of a total of 244 patients with IBD and healthy controls as well as from matched blood and intestinal tissue of 59 patients with IBD and disease controls. We further characterised specific T cell clonotypes via single-cell RNAseq.ResultsWe identified a group of clonotypes, characterised by semi-invariant TCR alpha chains, to be significantly enriched in the blood of patients with Crohn’s disease (CD) and particularly expanded in the CD8+ T cell population. Single-cell RNAseq data showed an innate-like phenotype of these cells, with a comparable gene expression to unconventional T cells such as mucosal associated invariant T and natural killer T (NKT) cells, but with distinct TCRs.ConclusionsWe identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population. The potential implications of this population for CD or a subset thereof remain to be elucidated, and the immunophenotype and antigen reactivity of CAIT cells need further investigations in future studies.

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Section: Discussionmentioning

confidence: 89%

A novel unconventional T cell population enriched in Crohn’s disease

Rosati

Martini

Pogorelyy

et al. 2022

Gut

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“…Recent experimental evidence has demonstrated that NKT cells are capable of recognizing drug-like small molecules that are presented through a CD1d restricted pathway. 33 The role of nonconventional T-cells will be further discussed in following sections.…”

Section: Stevens-johnson Syndrome and Toxic Epidermalmentioning

confidence: 99%

“…133 Further studies using PPBF analogues resembling sulfonamides were evaluated but these studies failed to show activation of the ABd TCR (type II NKT cell clone) and the NKT15 TCR (type I NKT cell clone). 33 However, it is possible that other clones of the type I or II have a better affinity toward these compounds. Interestingly, when the halogenated derivative of PPBF was loaded with a CD1d tetramer, αβ T-cells and γδ Tcells were detected.…”

Section: Brief Description Of Nonconventional T-cells Discovered In 1...mentioning

confidence: 99%

“…Natural killer T-cells (NKT), a class of nonconventional T-cell, have been detected in inflamed lesions of SJS/TEN patients. Recent experimental evidence has demonstrated that NKT cells are capable of recognizing drug-like small molecules that are presented through a CD1d restricted pathway . The role of nonconventional T-cells will be further discussed in following sections.…”

Section: Clinical Manifestations Of Drug Hypersensitivity Reactionsmentioning

confidence: 99%

“…The chemical compound phenyl pentamethyldihydrobenzofuran-sulfonate (PPBF) was able to stimulate a type II NKT (V24-) cell line in a CD1d-dependent manner, where the sulfonate moiety seemed to be of particular importance for cell recognition . Further studies using PPBF analogues resembling sulfonamides were evaluated but these studies failed to show activation of the ABd TCR (type II NKT cell clone) and the NKT15 TCR (type I NKT cell clone) . However, it is possible that other clones of the type I or II have a better affinity toward these compounds.…”

Section: Activation Of Nonconventional T-cells By Small Moleculesmentioning

confidence: 99%

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Advances in Our Understanding of the Interaction of Drugs with T-cells: Implications for the Discovery of Biomarkers in Severe Cutaneous Drug Reactions

Hernandez-Jaimes

Cazares-Olvera

Line

et al. 2022

Chem. Res. Toxicol.

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Drugs can activate different cells of the immune system and initiate an immune response that can lead to life-threatening diseases collectively known as severe cutaneous adverse reactions (SCARs). Antibiotics, anticonvulsants, and antiretrovirals are involved in the development of SCARs by the activation of αβ naïve T-cells. However, other subsets of lymphocytes known as nonconventional T-cells with a limited T-cell receptor repertoire and innate and adaptative functions also recognize drugs and drug-like molecules, but their role in the pathogenesis of SCARs has only just begun to be explored. Despite 30 years of advances in our understanding of the mechanisms in which drugs interact with T-cells and the pathways for tissue injury seen during T-cell activation, at present, the development of useful clinical biomarkers for SCARs or predictive preclinical in vitro assays that could identify immunogenic moieties during drug discovery is an unmet goal. Therefore, the present review focuses on (i) advances in the understanding of the pathogenesis of SCARs reactions, (ii) a description of the interaction of drugs with conventional and nonconventional T-cells, and (iii) the current state of soluble blood circulating biomarker candidates for SCARs.

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