Abstract:Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1… Show more
“…Site-directed mutagenesis was subsequently performed on the TCRα-chain to yield a complete GEM1 TCRα sequence (TRAV1-2, accession JQ778263.1), using the following primers: forward 5'-GCCGTGC-GGGTCACCGGCGGCT-3', reverse 5'-AGCCGCCGGTGACCCGCACGGC-3'. LDN5-TCRα and TCRβ (TRAV17/TRBV4-1) was cloned as previously described (47).…”
Section: Immunohistochemistrymentioning
confidence: 99%
“…Soluble TCR and TCR dextramers: Generation of TCR heterodimers were performed as previously described (47). Briefly, the extracellular domains of TCRα and TCRβ chains were produced in E.coli Rosetta as inclusion bodies after cloning into the bacterial expression vector pGMT7.…”
Section: Submission Pdfmentioning
confidence: 99%
“…To produce stably refolded disulphide-linked heterodimers, cysteines were incorporated into the TCRα-and β-chain constant domains, by replacing Thr48 and Ser57, respectively. The disulphide-linked GEM18-TCR αβ heterodimers were expressed, refolded, and purified as previously described (47). Refolded and purified TCR was assessed by a reducing and non-reducing SDS/PAGE gel analysis.…”
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 |
“…Site-directed mutagenesis was subsequently performed on the TCRα-chain to yield a complete GEM1 TCRα sequence (TRAV1-2, accession JQ778263.1), using the following primers: forward 5'-GCCGTGC-GGGTCACCGGCGGCT-3', reverse 5'-AGCCGCCGGTGACCCGCACGGC-3'. LDN5-TCRα and TCRβ (TRAV17/TRBV4-1) was cloned as previously described (47).…”
Section: Immunohistochemistrymentioning
confidence: 99%
“…Soluble TCR and TCR dextramers: Generation of TCR heterodimers were performed as previously described (47). Briefly, the extracellular domains of TCRα and TCRβ chains were produced in E.coli Rosetta as inclusion bodies after cloning into the bacterial expression vector pGMT7.…”
Section: Submission Pdfmentioning
confidence: 99%
“…To produce stably refolded disulphide-linked heterodimers, cysteines were incorporated into the TCRα-and β-chain constant domains, by replacing Thr48 and Ser57, respectively. The disulphide-linked GEM18-TCR αβ heterodimers were expressed, refolded, and purified as previously described (47). Refolded and purified TCR was assessed by a reducing and non-reducing SDS/PAGE gel analysis.…”
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 |
“…CD1b-autoreactive T cells can recognize phospholipids (17,19), and a higher frequency of sulfatide and monosialotetrahexosylganglioside-specific (GM1-specific) T cells was detected in multiple sclerosis patients compared with normal controls (26). Moreover, CD1c-restricted T cells specific for cholesteryl esters have recently been identified (31). Finally, most CD1d-restricted NKT cells also exhibit autoreactivity and A large proportion of human T cells are autoreactive to group 1 CD1 proteins, which include CD1a, CD1b, and CD1c.…”
“…29 In addition, recent studies have shown that CD1a-restricted human T cell clones recognize skin-derived apolar oils and phospholipids; autoreactive CD1b-restricted human T cell clones recognize a range of phospholipids, whereas CD1c-reactive clones can bind cholesterol and its esters. [31][32][33] Considering that these lipids accumulate in most tumors, it is imperative to explore the role of autoreactive group 1 CD1-restricted T cells in tumor immunity. This would shed light on the potential use of these T cells in cancer immunotherapy.…”
Adoptive immunotherapy for cancer treatment is an emerging field of study. Till now, several tumorderived, peptide-specific T cell responses have been harnessed for treating cancers. However, the contribution of lipid-specific T cells in tumor immunity has been understudied. CD1 molecules, which present self-and foreign lipid antigens to T cells, are divided into group 1 (CD1a, CD1b, and CD1c) and group 2 (CD1d). Although the role of CD1d-restricted natural killer T cells (NKT) in several tumor models has been well established, the contribution of group 1 CD1-restricted T cells in tumor immunity remains obscure due to the lack of group 1 CD1 expression in mice. In this study, we used a double transgenic mouse model expressing human group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, self-lipid reactive T cell receptor (HJ1Tg) to study the potential role of group 1 CD1-restricted autoreactive T cells in antitumor response. We found that HJ1 T cells recognized phospholipids and responded more potently to lipid extracted from tumor cells than the equivalent amount of lipids extracted from normal cells. Additionally, the autoreactivity of HJ1 T cells was enhanced upon treatment with various intracellular tolllike receptor (TLR) agonists, including CpG oligodeoxynucleotides (ODN), R848, and poly (I:C). Interestingly, the adoptive transfer of HJ1 T cells conferred protection against the CD1b-transfected murine T cell lymphoma (RMA-S/CD1b) and CpG ODN enhanced the antitumor effect. Thus, this study, for the first time, demonstrates the antitumor potential of CD1b-autoreactive T cells and their potential use in adoptive immunotherapy.
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