A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1

T cell receptors (TCRs) recognize antigens presented by major histocompatibility complex (MHC) and MHC class I–like molecules. We describe a diverse population of human γδ T cells isolated from peripheral blood and tissues that exhibit autoreactivity to the monomorphic MHC-related protein 1 (MR1). The crystal structure of a γδTCR–MR1–antigen complex starkly contrasts with all other TCR–MHC and TCR–MHC-I-like complex structures. Namely, the γδTCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 α3 domain. A similar pattern of reactivity was observed for diverse MR1-restricted γδTCRs from multiple individuals. Accordingly, we simultaneously report MR1 as a ligand for human γδ T cells and redefine the parameters for TCR recognition.

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Immunological studies of T-cell receptors. II. Limited polymorphism of idiotypic determinants on T-cell receptors specific for major histocompatibility complex alloantigens.

Journal of Experimental Medicine ◽

10.1084/jem.149.1.234 ◽

1979 ◽

Vol 149 (1) ◽

pp. 234-243 ◽

Cited By ~ 33

Author(s):

D Bellgrau ◽

D B Wilson

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Parental Strain ◽

Germ Line ◽

Third Party ◽

Cell Receptors ◽

Histocompatibility Complex ◽

Cell Mediated Immune Response ◽

Different Strains

These studies explore the extent of genetic polymorphism in the expression of anti-MHC receptors by T cells in different strains of rats. This question was approached with the use of the model of specifically induced GVH resistance in F1 rats which has been shown to reflect a specific T-cell mediated immune response against parental strain T cell anti-MHC receptors specific for host alloantigens. When A/B F1 rats derived from MHC incompatibile matings are immunized with lymphocytes from one parental strain (A they display a specific resistance to anti-B GVH reactivity caused by T cells from that parental strain, but not anti-AGVH reactions from the other. In addition, they resist anti-B GHV reactivity by T cells from third-party donors (C, D, E,...), a finding taken to indicate that the idiotypes of anti-MHC receptors on T cells, recognized by other T cells, show little or no polymorphism. This conclusion suggests that anti-MHC receptors are shared in the species and may be encoded, at least partially, by germ-line genes.

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Presentation of Toxoplasma gondii Antigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells

Infection and Immunity ◽

10.1128/iai.00954-07 ◽

2007 ◽

Vol 75 (11) ◽

pp. 5200-5209 ◽

Cited By ~ 61

Author(s):

Florence Dzierszinski ◽

Marion Pepper ◽

Jason S. Stumhofer ◽

David F. LaRosa ◽

Emma H. Wilson ◽

...

Keyword(s):

T Cells ◽

Major Histocompatibility Complex ◽

T Cell ◽

Antigen Processing ◽

Cell Types ◽

T Cell Response ◽

Complex Class ◽

Mhc I ◽

Histocompatibility Complex ◽

Antigen Presenting

ABSTRACT Challenge with the intracellular protozoan parasite Toxoplasma gondii induces a potent CD8+ T-cell response that is required for resistance to infection, but many questions remain about the factors that regulate the presentation of major histocompatibility complex class I (MHC-I)-restricted parasite antigens and about the role of professional and nonprofessional accessory cells. In order to address these issues, transgenic parasites expressing ovalbumin (OVA), reagents that track OVA/MHC-I presentation, and OVA-specific CD8+ T cells were exploited to compare the abilities of different infected cell types to stimulate CD8+ T cells and to define the factors that contribute to antigen processing. These studies reveal that a variety of infected cell types, including hematopoietic and nonhematopoietic cells, are capable of activating an OVA-specific CD8+ T-cell hybridoma, and that this phenomenon is dependent on the transporter associated with antigen processing and requires live T. gondii. Several experimental approaches indicate that T-cell activation is a consequence of direct presentation by infected host cells rather than cross-presentation. Surprisingly, nonprofessional antigen-presenting cells (APCs) were at least as efficient as dendritic cells at activating this MHC-I-restricted response. Studies to assess whether these cells are involved in initiation of the CD8+ T-cell response to T. gondii in vivo show that chimeric mice expressing MHC-I only in nonhematopoietic compartments are able to activate OVA-specific CD8+ T cells upon challenge. These findings associate nonprofessional APCs with the initial activation of CD8+ T cells during toxoplasmosis.

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S-acylation targets ORAI1 channels to lipid rafts for efficient Ca2+ signaling by T cell receptors at the immune synapse

10.1101/2021.02.03.429577 ◽

2021 ◽

Author(s):

Amado Carreras-Sureda ◽

Laurence Abrami ◽

Ji-Hee Kim ◽

Maud Frieden ◽

Monica Didier ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Hek 293 ◽

Immune Synapse ◽

Cell Receptors ◽

Channel Assembly ◽

And Function ◽

Antigen Presenting ◽

Reduced Mobility

AbstractEfficient immune responses require Ca2+ fluxes across ORAI1 channels during engagement of T cell receptors (TCR) at the immune synapse (IS) between T cells and antigen presenting cells. Here, we show that ZDHHC20-mediated S-acylation of the ORAI1 channel at residue Cys143 is required for TCR assembly and signaling at the IS. Cys143 mutations reduced ORAI1 currents and store-operated Ca2+ entry in HEK-293 cells and nearly abrogated long-lasting Ca2+ elevations, NFATC1 translocation, and IL-2 secretion evoked by TCR engagement in Jurkat T cells. The acylation-deficient channel had reduced mobility in lipids, accumulated in cholesterol-poor domains, formed tiny clusters, failed to reach the IS and unexpectedly also prevented TCR recruitment to the IS. Our results establish S-acylation as a critical regulator of ORAI1 channel assembly and function at the IS and reveal that local Ca2+ fluxes are required for TCR recruitment to the synapse.

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S-acylation by ZDHHC20 targets ORAI1 channels to lipid rafts for efficient Ca2+ signaling by Jurkat T cell receptors at the immune synapse

eLife ◽

10.7554/elife.72051 ◽

2021 ◽

Vol 10 ◽

Author(s):

Amado Carreras-Sureda ◽

Laurence Abrami ◽

Kim Ji-Hee ◽

Wen-An Wang ◽

Christopher Henry ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Hek 293 ◽

Immune Synapse ◽

Cell Receptors ◽

Channel Trafficking ◽

293 Cells ◽

And Function ◽

Antigen Presenting

Efficient immune responses require Ca2+ fluxes across ORAI1 channels during engagement of T cell receptors (TCR) at the immune synapse (IS) between T cells and antigen presenting cells. Here, we show that ZDHHC20-mediated S-acylation of the ORAI1 channel at residue Cys143 promotes TCR recruitment and signaling at the IS. Cys143 mutations reduced ORAI1 currents and store-operated Ca2+ entry in HEK-293 cells and nearly abrogated long-lasting Ca2+ elevations, NFATC1 translocation, and IL-2 secretion evoked by TCR engagement in Jurkat T cells. The acylation-deficient channel remained in cholesterol-poor domains upon enforced ZDHHC20 expression and was recruited less efficiently to the IS along with actin and TCR. Our results establish S-acylation as a critical regulator of ORAI1 channel trafficking and function at the IS and reveal that ORAI1 S-acylation enhances TCR recruitment to the synapse.

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A blend of broadly-reactive and pathogen-selected Vγ4 Vδ1 T cell receptors confer broad bacterial reactivity of resident memory γδ T cells

Mucosal Immunology ◽

10.1038/s41385-021-00447-x ◽

2021 ◽

Author(s):

Camille Khairallah ◽

Julie A. Bettke ◽

Oleksandr Gorbatsevych ◽

Zhijuan Qiu ◽

Yue Zhang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Γδ T Cells ◽

Cell Receptors

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Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1605399113 ◽

2016 ◽

Vol 113 (40) ◽

pp. E5916-E5924 ◽

Cited By ~ 86

Author(s):

Yunmin Jung ◽

Inbal Riven ◽

Sara W. Feigelson ◽

Elena Kartvelishvily ◽

Kazuo Tohya ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Three Dimensional ◽

Spatial Relation ◽

Protein Distribution ◽

Cell Receptors ◽

Human T Cells ◽

Antigen Presenting

Leukocyte microvilli are flexible projections enriched with adhesion molecules. The role of these cellular projections in the ability of T cells to probe antigen-presenting cells has been elusive. In this study, we probe the spatial relation of microvilli and T-cell receptors (TCRs), the major molecules responsible for antigen recognition on the T-cell membrane. To this end, an effective and robust methodology for mapping membrane protein distribution in relation to the 3D surface structure of cells is introduced, based on two complementary superresolution microscopies. Strikingly, TCRs are found to be highly localized on microvilli, in both peripheral blood human T cells and differentiated effector T cells, and are barely found on the cell body. This is a decisive demonstration that different types of T cells universally localize their TCRs to microvilli, immediately pointing to these surface projections as effective sensors for antigenic moieties. This finding also suggests how previously reported membrane clusters might form, with microvilli serving as anchors for specific T-cell surface molecules.

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Clonal expansion of γδ T cells expressing two distinct T‐cell receptors

British Journal of Haematology ◽

10.1046/j.1365-2141.1996.d01-1779.x ◽

1996 ◽

Vol 94 (1) ◽

pp. 62-64 ◽

Cited By ~ 9

Author(s):

Thomas Hinz ◽

Sibylle Marx ◽

Christoph Nerl ◽

Dieter Kabelitz

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Γδ T Cells ◽

Clonal Expansion ◽

Cell Receptors

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

Journal of Experimental Medicine ◽

10.1084/jem.20110665 ◽

2011 ◽

Vol 208 (9) ◽

pp. 1741-1747 ◽

Cited By ~ 89

Author(s):

Anne G. Kasmar ◽

Ildiko van Rhijn ◽

Tan-Yun Cheng ◽

Marie Turner ◽

Chetan Seshadri ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Direct Detection ◽

Ex Vivo ◽

T Cell Repertoire ◽

Cell Repertoire ◽

Cell Receptors ◽

Cell Staining ◽

Antigen Presenting

Microbial lipids activate T cells by binding directly to CD1 and T cell receptors (TCRs) or by indirect effects on antigen-presenting cells involving induction of lipid autoantigens, CD1 transcription, or cytokine release. To distinguish among direct and indirect mechanisms, we developed fluorescent human CD1b tetramers and measured T cell staining. CD1b tetramer staining of T cells requires glucose monomycolate (GMM) antigens, is specific for TCR structure, and is blocked by a recombinant clonotypic TCR comprised of TRAV17 and TRBV4-1, proving that CD1b–glycolipid complexes bind the TCR. GMM-loaded tetramers brightly stain a small subpopulation of blood-derived cells from humans infected with Mycobacterium tuberculosis, providing direct detection of a CD1b-reactive T cell repertoire. Polyclonal T cells from patients sorted with tetramers are activated by GMM antigens presented by CD1b. Whereas prior studies emphasized CD8+ and CD4−CD8− CD1b-restricted clones, CD1b tetramer-based studies show that nearly all cells express the CD4 co-receptor. These findings prove a cognate mechanism whereby CD1b–glycolipid complexes bind to TCRs. CD1b tetramers detect a natural CD1b-restricted T cell repertoire ex vivo with unexpected features, opening a new investigative path to study the human CD1 system.

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Can Glycosylation Mask the Detection of MHC Expressing p53 Peptides by T Cell Receptors?

Biomolecules ◽

10.3390/biom11071056 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1056

Author(s):

Thanh Binh Nguyen ◽

David P. Lane ◽

Chandra S. Verma

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Human Leukocyte ◽

Cell Receptors ◽

Leukocyte Antigen ◽

Endogenous Peptides ◽

Histocompatibility Complex ◽

Normal Individuals

Proteins of the major histocompatibility complex (MHC) class I, or human leukocyte antigen (HLA) in humans interact with endogenous peptides and present them to T cell receptors (TCR), which in turn tune the immune system to recognize and discriminate between self and foreign (non-self) peptides. Of especial importance are peptides derived from tumor-associated antigens. T cells recognizing these peptides are found in cancer patients, but not in cancer-free individuals. What stimulates this recognition, which is vital for the success of checkpoint based therapy? A peptide derived from the protein p53 (residues 161–169 or p161) was reported to show this behavior. T cells recognizing this unmodified peptide could be further stimulated in vitro to create effective cancer killing CTLs (cytotoxic T lymphocytes). We hypothesize that the underlying difference may arise from post-translational glycosylation of p161 in normal individuals, likely masking it against recognition by TCR. Defects in glycosylation in cancer cells may allow the presentation of the native peptide. We investigate the structural consequences of such peptide glycosylation by investigating the associated structural dynamics.

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