CD1b Tetramers Identify T Cells that Recognize Natural and Synthetic Diacylated Sulfoglycolipids from Mycobacterium tuberculosis

James, Cyan; Yu, Krystle K. Q.; Gilleron, Martine; Prandi, Jacques; Yedulla, Vijayendar R.; Moleda, Zuzanna Z.; Diamanti, Eleonora; Khan, M. Gufran; Aggarwal, Varinder K.; Reijneveld, Josephine F.; Reinink, Peter; Lenz, Stefanie; Emerson, Ryan; Scriba, Thomas J.; Souter, Michael N T; Godfrey, Dale I.; Pellicci, Daniel G.; Moody, D. Branch; Minnaard, Adriaan J.; Seshadri, Chetan; Rhijn, Ildiko Van

doi:10.1016/j.chembiol.2018.01.006

Cited by 23 publications

(38 citation statements)

References 57 publications

(91 reference statements)

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“…The development of CD1b tetramers for GMM, SGLs, and MA have enabled the isolation of mycolipid-specific T cells to study the T cell receptor (TCR) repertoire and functional diversity directly ex vivo (35)(36)(37)(38)(39)(40). TCR diversity among T cells specific for mycolipids has been best studied using GMM as the model antigen.…”

Section: Mycolipid-specific T Cell Receptor Diversitymentioning

confidence: 99%

T Cell Responses to Mycobacterial Glycolipids: On the Spectrum of “Innateness”

James

Seshadri

2020

Front. Immunol.

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Diseases due to mycobacteria, including tuberculosis, leprosy, and Buruli ulcer, rank among the top causes of death and disability worldwide. Animal studies have revealed the importance of T cells in controlling these infections. However, the specific antigens recognized by T cells that confer protective immunity and their associated functions remain to be definitively established. T cells that respond to mycobacterial peptide antigens exhibit classical features of adaptive immunity and have been well-studied in humans and animal models. Recently, innate-like T cells that recognize lipid and metabolite antigens have also been implicated. Specifically, T cells that recognize mycobacterial glycolipid antigens (mycolipids) have been shown to confer protection to tuberculosis in animal models and share some biological characteristics with adaptive and innate-like T cells. Here, we review the existing data suggesting that mycolipid-specific T cells exist on a spectrum of "innateness," which will influence how they can be leveraged to develop new diagnostics and vaccines for mycobacterial diseases.

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Section: Mycolipid-specific T Cell Receptor Diversitymentioning

confidence: 99%

T Cell Responses to Mycobacterial Glycolipids: On the Spectrum of “Innateness”

James

Seshadri

2020

Front. Immunol.

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“…High levels of CD1b are present on DC's or induced on monocytes differentiating into DCs [7,8], where it presents self and foreign lipids to T cells. Many foreign lipids that are known to be presented by CD1b are derived from mycobacteria or closely related actinobacteria, such as glucose monomycolate, glycerol monomycolate [9][10][11], mycolic acid [5,12,13], and diacylated sulfoglycolipids [14,15]. Also, some self-lipids from mammalian cells are presented by CD1b, including phosphatidylglycerol, phosphatidic acid (PA), phosphatidylethanolamine, phosphatidylinositol, and gangliosides [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

CD1b presents self and Borrelia burgdorferi diacylglycerols to human T cells

et al. 2019

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Lyme disease is a common multisystem disease caused by infection with a tick‐transmitted spirochete, Borrelia burgdorferi and related Borrelia species. The monoglycosylated diacylglycerol known as B. burgdorferi glycolipid II (BbGL‐II) is a major target of antibodies in sera from infected individuals. Here, we show that CD1b presents BbGL‐II to human T cells and that the TCR mediates the recognition. However, we did not detect increased frequency of CD1b‐BbGL‐II binding T cells in the peripheral blood of Lyme disease patients compared to controls. Unexpectedly, mapping the T cell specificity for BbGL‐II‐like molecules using tetramers and activation assays revealed a concomitant response to CD1b‐expressing APCs in absence of BbGL‐II. Further, among all major classes of self‐lipid tested, BbGL‐II responsive TCRs show strong cross‐reactivity to diacylglycerol, a self‐lipid antigen with structural similarities to BbGL‐II. Extending prior work on MHC and CD1b, CD1c, and CD1d proteins, this study provides evidence for cross‐reactive CD1b‐restricted T cell responses to bacterial and self‐antigens, and identifies chemically defined targets for future discovery of self and foreign antigen cross‐reactive T cells.

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“…We first determined which co-receptor was expressed by SGL-specific T cells directly ex vivo using CD1b tetramers loaded with a biologically validated synthetic analog of SGL (James et al, 2018). We examined peripheral blood mononuclear cells (PBMC) derived from five U.S. healthy donors, five South African adolescents with latent tuberculosis infection (LTBI), and five South African adolescents without LTBI (Supplemental Table 1, Supplemental Table 2, and Supplemental Figure 1) (Mahomed et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…To ensure accurate identification of antigen-specific T cells, we used a dual-tetramer labelling strategy incorporating SGL-CD1b tetramer labeled with two distinct fluorochromes and defined SGL-specific T cells as staining with both tetramers while being unlabeled by a mock-loaded CD1b tetramer (Figure 1A, Supplemental Figure 1). Gates defining SGL-CD1b tetramer-positive cells were set based on staining an SGL-specific T cell line and fluorescence minus one (FMO) controls (Figure 1A) (James et al, 2018). Representative staining from one individual is shown (Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells

James

Aguilar

et al. 2020

Preprint

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CD4 and CD8 co-receptors define distinct lineages of T cells restricted by major histocompatibility complex (MHC) Class II and I molecules, respectively. Co-receptors interact with the T cell receptor (TCR) at the surface of MHC-restricted T cells to facilitate antigen recognition, thymic selection, and functional differentiation. T cells also recognize lipid antigens presented by CD1 molecules, but the role that CD4 and CD8 play in lipid antigen recognition is unknown. We studied the effect of CD4 and CD8 on the avidity, activation, and function of T cells specific for two CD1b-presented mycobacterial lipid antigens, glucose monomycolate (GMM) and diacylated sulfoglycolipids (SGL). In a human cohort study using SGL-loaded CD1b tetramers, we discovered a hierarchy among SGL-specific T cells in which T cells expressing the CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity (MFI) than CD4-CD8- T cells. To determine the role of the TCR co-receptor in lipid antigen recognition, we exogenously expressed GMM and SGL-specific TCRs in Jurkat or polyclonal T cells and quantified tetramer staining and activation thresholds. Transduced CD4+ primary T cells bound the lipid-loaded CD1b tetramer with a higher MFI than CD8+ primary T cells, and transduced CD8+ Jurkat cells bound the SGL-CD1b tetramer with higher MFI than CD4-CD8- Jurkat cells. The presence of either co-receptor also decreased the threshold for IFN-γ secretion. Further, co-receptor expression increased surface expression of CD3ε, suggesting a mechanism for increased tetramer binding and activation. Finally, we used single-cell sequencing to define the TCR repertoire and ex vivo functional profiles of SGL-specific T cells from individuals with M.tb disease. We found that CD8+ T cells specific for SGL express canonical markers associated with cytotoxic T lymphocytes, while CD4+ T cells could be classified as T regulatory or T follicular helper cells. Among SGL-specific T cells, only those expressing the CD4 co-receptor also expressed Ki67, suggesting that they were actively proliferating at the time of sample collection. Together, these data reveal that expression of CD4 and CD8 co-receptor modulates TCR avidity for lipid antigen, leading to functional diversity and differences in in vivo proliferation during M.tb disease.

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CD1b Tetramers Identify T Cells that Recognize Natural and Synthetic Diacylated Sulfoglycolipids from Mycobacterium tuberculosis

Cited by 23 publications

References 57 publications

T Cell Responses to Mycobacterial Glycolipids: On the Spectrum of “Innateness”

T Cell Responses to Mycobacterial Glycolipids: On the Spectrum of “Innateness”

CD1b presents self and Borrelia burgdorferi diacylglycerols to human T cells

CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells

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