CD1-Restricted T Cells in Host Defense to Infectious Diseases

Behar, Samuel M.; Porcelli, Steven A.

doi:10.1007/978-3-540-69511-0_9

Cited by 84 publications

(90 citation statements)

References 144 publications

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“…Crosstalk between the two cell types involves CD40/CD40L interactions but does not The adjuvant effects of iNKT cells, together with their cytotoxic activities and capacity to secrete diverse cytokines, and the ease by which these cells can be expanded using conserved antigens have placed these cells as important immunomodulators in the tissues and potential targets for immunotherapy. Therapeutic activation of iNKT cells in murine models can prevent tumor growth [182][183][184], ameliorate autoimmune [185,186] and metabolic [187] disease, and protect against microbial infection [188]. Numerical and functional iNKT cell deficiencies have been reported in a number of human diseases [189][190][191][192].…”

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confidence: 99%

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

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confidence: 99%

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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“…Early studies indicated that the majority of T cell clones specific for lipid Ags were negative for CD4 and CD8 (17,18,23), but meanwhile the universe of lipidresponsive T cells has expanded to CD4 ϩ (24) and CD8 ϩ lymphocytes (25)(26)(27). Cells responding to nonprotein Ags are likely to be important in protection against tuberculosis because they produce Th1 cytokines, lyse M.Tb-infected cells, and kill the intracellular pathogen (16). Although all these results were obtained by analyzing T cell lines and clones, only one study has demonstrated that there is a reservoir of CD1-restricted lipid responsive T cells in the peripheral blood of M.Tb-primed individuals (28).…”

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confidence: 99%

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

Bastian¹,

Braun

Bruns³

et al. 2008

The Journal of Immunology

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In searching for immunogenic molecules with the potential to induce protective immune responses against tuberculosis, we developed an ex vivo model to study frequency, phenotype, and effector functions of human T lymphocytes recognizing hydrophobic Ags of Mycobacterium tuberculosis (M.Tb). To obtain unbiased results, we characterized T lymphocytes responding to a crude cell wall extract (chloroform methanol extract of M.Tb (M.Tb-CME)) containing a broad spectrum of mycobacterial glycolipids and lipopeptides. A significant proportion of T lymphocytes recognized M.Tb-CME (290 IFN-γ+ T cells/105 PBMCs) and developed to effector memory cells as determined by the expression of CD45RO and the chemokine receptors CXCR3 and CCR5. Expanded lymphocytes fulfilled all criteria required for an efficient immune response against tuberculosis: 1) release of macrophage-activating Th1 cytokines and chemokines required for the spatial organization of local immune responses, 2) cytolytic activity against Ag-pulsed macrophages, and 3) recognition of infected macrophages and killing of the intracellular bacteria. Phenotypically, M.Tb-CME-expanded cells were CD4+ and MHC class II restricted, challenging current concepts that cytotoxic and antimicrobial effector cells are restricted to the CD8+ T cell subset. Pretreatment of M.Tb-CME with protease or chemical delipidation abrogated the biological activity, suggesting that responses were directed toward mycobacterial lipopeptides. These findings suggest that lipidated peptides are presented by M.Tb-infected macrophages and elicit CD4+ cytolytic and antimicrobial T lymphocytes. Our data support an emerging concept to include hydrophobic microbial Ags in vaccines against tuberculosis.

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“…However, the CD1 proteins have undergone significant structural evolution to bind and present lipid molecules instead of peptides (8). The CD1-restricted T cells have been implicated in a diverse array of immune functions including host defense against pathogens, immune regulation, and autoimmunity (9,10). In addition, foreign lipids derived from bacteria, as well as self-lipid antigens, have been described for CD1 (11)(12)(13)(14)(15)(16).…”

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confidence: 99%

The crystal structure of avian CD1 reveals a smaller, more primordial antigen-binding pocket compared to mammalian CD1

Zajonc

Striegl

Dascher

et al. 2008

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

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The molecular details of glycolipid presentation by CD1 antigenpresenting molecules are well studied in mammalian systems. However, little is known about how these non-classical MHC class I (MHCI) molecules diverged from the MHC locus to create a more complex, hydrophobic binding groove that binds lipids rather than peptides. To address this fundamental question, we have determined the crystal structure of an avian CD1 (chCD1-2) that shares common ancestry with mammalian CD1 from Ϸ310 million years ago. The chCD1-2 antigen-binding site consists of a compact, narrow, central hydrophobic groove or pore rather than the more open, 2-pocket architecture observed in mammalian CD1s. Potential antigens then would be restricted in size to single-chain lipids or glycolipids. An endogenous ligand, possibly palmitic acid, serves to illuminate the mode and mechanism of ligand interaction with chCD1-2. The palmitate alkyl chain is inserted into the relatively shallow hydrophobic pore; its carboxyl group emerges at the receptor surface and is stabilized by electrostatic and hydrogen bond interactions with an arginine residue that is conserved in all known CD1 proteins. In addition, other novel features, such as an A loop that interrupts and segments the normally long, continuous ␣1 helix, are unique to chCD1-2 and contribute to the unusually narrow binding groove, thereby limiting its size. Because birds and mammals share a common ancestor, but the rate of evolution is slower in birds than in mammals, the chCD1-2-binding groove probably represents a more primordial CD1-binding groove.evolution ͉ glycolipid

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CD1-Restricted T Cells in Host Defense to Infectious Diseases

Cited by 84 publications

References 144 publications

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

The crystal structure of avian CD1 reveals a smaller, more primordial antigen-binding pocket compared to mammalian CD1

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