CD1b tetramers bind αβ T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans

Kasmar, Anne; Rhijn, Ildiko Van; Cheng, Tan Yun; Turner, Marie T.; Seshadri, Chetan; Schiefner, A.; Kalathur, Ravi C.; Annand, John W.; Jong, Annemieke de; Shires, John; León, Luis E. De; Brenner, Michael B.; Wilson, Ian A.; Altman, John D.; Moody, D. Branch

doi:10.1084/jem.20110665

Cited by 115 publications

(143 citation statements)

References 40 publications

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“…ϩ (14). To determine the phenotype of GMM-specific T cells detected in our monkey model, PBMCs derived from the 4 BCG-vaccinated monkeys were stimulated in vitro with either the GMM liposome or empty liposome and subjected to a multicolor flow cytometric analysis for intracellular cytokines and surface markers.…”

Section: Resultsmentioning

confidence: 99%

“…Circulating GMM-specific T cells are detectable in patients with tuberculosis (14), but it remains to be examined if these cells are able to extravasate and gain access to the site of infection. To address this, the GMM-specific T cell line derived from the MM552 monkey was labeled with CFSE and injected intravenously back into the same subject, i.e., MM552.…”

Section: Resultsmentioning

confidence: 99%

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Major T Cell Response to a Mycolyl Glycolipid Is Mediated by CD1c Molecules in Rhesus Macaques

et al. 2013

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c Human CD1b molecules contain a maze of hydrophobic pockets and a tunnel capable of accommodating the unusually long, branched acyl chain of mycolic acids, an essential fatty acid component of the cell wall of mycobacteria. It has been accepted that CD1b-bound mycolic acids constitute a scaffold for mycolate-containing (glyco)lipids stimulating CD1b-restricted T cells. Remarkable homology in amino acid sequence is observed between human and monkey CD1b molecules, and indeed, monkey CD1b molecules are able to bind glucose monomycolate (GMM), a glucosylated species of mycolic acids, and present it to specific human T cells in vitro. Nevertheless, we found, unexpectedly, that Mycobacterium bovis bacillus Calmette-Guerin (BCG)-vaccinated monkeys exhibited GMM-specific T cell responses that were restricted by CD1c rather than CD1b molecules. GMM-specific, CD1c-restricted T cells were detected in the circulation of all 4 rhesus macaque monkeys tested after but not before vaccination with BCG. The circulating GMM-specific T cells were detected broadly in both CD4؉ and CD8 ؉ cell populations, and upon antigenic stimulation, a majority of the GMM-specific T cells produced both gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣), two major host protective cytokines functioning against infection with mycobacteria. Furthermore, the GMM-specific T cells were able to extravasate and approach the site of infection where CD1c ؉ cells accumulated. These observations indicate a previously inconceivable role for primate CD1c molecules in eliciting T cell responses to mycolate-containing antigens.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Major T Cell Response to a Mycolyl Glycolipid Is Mediated by CD1c Molecules in Rhesus Macaques

et al. 2013

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“…To bypass confounding effects of DAG on antigen-presenting cells and focus on the interactions with the glycolipid antigen, glucose monomycolate (GMM), we used cell-free assays. These T cells respond to GMM with an average alkyl chain length of C80 (C80 GMM) or C32 (C32 GMM) based on the ability of GMM to mediate a physical interaction of CD1b with the clonotypic TCR (28,30). Therefore, we measured IFN-γ release by the CD1b-restricted, GMM-reactive T-cell line LDN5 as a measure of antigen presentation.…”

Section: Cd1b Captures Nonpolar Lipids With Early Retention Timementioning

confidence: 99%

Discovery of deoxyceramides and diacylglycerols as CD1b scaffold lipids among diverse groove-blocking lipids of the human CD1 system

Huang

Cheng

Young

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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102

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Unlike the dominant role of one class II invariant chain peptide (CLIP) in blocking MHC class II, comparative lipidomics analysis shows that human cluster of differentiation (CD) proteins CD1a, CD1b, CD1c, and CD1d bind lipids corresponding to hundreds of diverse accurate mass retention time values. Although most ions were observed in association with several CD1 proteins, ligands binding selectively to one CD1 isoform allowed the study of how differing antigenbinding grooves influence lipid capture. Although the CD1b groove is distinguished by its unusually large volume (2,200 Å 3 ) and the T′ tunnel, the average mass of compounds eluted from CD1b was similar to that of lipids from CD1 proteins with smaller grooves. Elution of small ligands from the large CD1b groove might be explained if two small lipids bind simultaneously in the groove. Crystal structures indicate that all CD1 proteins can capture one antigen with its hydrophilic head group exposed for T-cell recognition, but CD1b structures show scaffold lipids seated below the antigen. We found that ligands selectively associated with CD1b lacked the hydrophilic head group that is generally needed for antigen recognition but interferes with scaffold function. Furthermore, we identified the scaffolds as deoxyceramides and diacylglycerols and directly demonstrate a function in augmenting presentation of a small glycolipid antigen to T cells. Thus, unlike MHC class II, CD1 proteins capture highly diverse ligands in the secretory pathway. CD1b has a mechanism for presenting either two small or one large lipid, allowing presentation of antigens with an unusually broad range of chain lengths.antigen presentation | Mycobacterium tuberculosis | cluster of differentiation 1

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“…Multiple Mtb lipids are presented by CD1 proteins to lipid-reactive αβ T cells, which are increasingly being recognised as important components of the host immune response (9)(10)(11)(12)(13). The CD1 family comprises five non-polymorphic MHC class-I-like proteins, CD1a, CD1b, CD1c, CD1d and CD1e, which present lipid-antigens to T cells at the surface of antigen presenting cells (APC), with the exception of CD1e (14).…”

Section: Introductionmentioning

confidence: 99%

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

Chancellor

Tocheva

Cave-Ayland

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Tuberculosis, caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in tuberculosis granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells. Mycobaterium tuberculosis | GEM T cells | CD1b | Mycolate lipids |

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CD1b tetramers bind αβ T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans

Abstract: Glucose monomycolate–loaded CD1b tetramers identify a subset of CD4+ T cells in patients with Mycobacterium tuberculosis infection.

Cited by 115 publications

References 40 publications

Major T Cell Response to a Mycolyl Glycolipid Is Mediated by CD1c Molecules in Rhesus Macaques

Major T Cell Response to a Mycolyl Glycolipid Is Mediated by CD1c Molecules in Rhesus Macaques

Discovery of deoxyceramides and diacylglycerols as CD1b scaffold lipids among diverse groove-blocking lipids of the human CD1 system

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

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