Aberrant T‐Cell Receptor Signalling of Interferon‐γ‐ and Tumour Necrosis Factor‐α‐Producing Cytotoxic CD8+ Vδ1/Vβ16 T Cells in a Patient with Chronic Neutropenia
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We previously found that the peripheral blood (PB) mononuclear cells (MCs) (PBMCs) of a patient with chronic neutropenia contained an expanded population of cytotoxic CD8+ T cells using a variable (V) region delta1 gene product in the T-cell receptor-alpha (TCR-alpha) polypeptide [Vdelta1-constant(C)alpha+ T cells]. Sequencing of polymerase chain reaction (PCR) amplification products have now revealed a productive Vdelta1/joining (J)alphaIGRJa03/Calpha rearrangement of the TCR-alpha gene, predominantly associated with a Vbeta16/Dbeta2.1/Jbeta2.1/Cbeta2 TCR-beta gene, in these cells. Furthermore, we detected a markedly deficient proliferative response of the patient PBMCs to triggering with monoclonal antibodies (MoAbs) to the CD3 molecule, contrasting with a substantial response to the Vbeta3, 12, 14, 15, 17 and 20-specific staphylococcal enterotoxin B (SEB) superantigen, suggesting defective TCR-mediated activation of the Vdelta1+/Vbeta16+ clone. Moreover, whereas triggering of Vdelta1- T cells cultured with interleukin-2 (IL-2) by MoAb to the CD3 molecule enhanced proliferation, Vdelta1-Calpha+ T cells were inhibited by MoAbs to either CD3 or Vdelta1. Vdelta1-Calpha+ T-cell clones spontaneously secrete interferon-gamma (IFN-gamma) and were further induced to release tumour necrosis factor (TNF-alpha) when triggered by anti-CD3 plus phorbol ester. Aberrant signalling by the clonotypic TCR together with the functional properties of the CD8+ Vdelta1+/Vbeta16+ clone may thus contribute to the immunohaematological abnormalities observed in this patient.Keywords:
clone (Java method)
Superantigen
Gene rearrangement
Gene rearrangement
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Abstract A cross-sectional PCR analysis of the TCR Vβ repertoires in HIV-1 seronegative controls and HIV-1 infected individuals with either clinically or immunologically defined AIDS [1] was performed to examine the proposed superantigen model for HIV-1 pathogenesis. In contrast to previous reports, we find neither uniform specific losses nor uniform clonal expansions of particular TCR Vβ gene families in subjects with AIDS. Instead our study, which was designed specifically to qualitatively determine the presence or absence of TCR Vβ families in both subject populations, indicates an overall diminution in the expression of TCR Vβ gene families in HIV-1 infected individuals with AIDS compared with controls. This is commensurate with the decrease in CD4 T cells in the AIDS population. Our data are therefore not directly suggestive of a common superantigen model of HIV-1 induced T cell clonal depletion or anergy, but instead emphasize a broad decrease in signals throughout the TCR Vβ repertoire in AIDS versus control groups. This random depletion in the TCR Vβ repertoire is most likely caused by aspects of HIV-1 pathogenesis other than virus- encoded superantigens.
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Abstract The TCR V beta element is pivotal for superantigen recognition; however, not all T cells bearing a particular V beta element respond to an individual superantigen. Recent evidence has indicated that the TCR V alpha element also contributes to recognition of superantigen/MHC class II complexes. To determine whether the TCR beta-chain junctional regions influence recognition of a superantigen encoded by mouse mammary tumor virus (MMTV) proviral integrant Mtv-1, we have analyzed these regions in T cells that have survived superantigen-mediated negative selection in B10.BR-Mtv-1 mice. Our data indicate: 1) no TCR J beta skewing, 2) no difference in the length of the third complementarity-determining region (CDR3), and 3) no outstanding structural features that are shared among the junctional regions of the V beta 3+ T cells that escape thymic clonal elimination in superantigen-expressing mice. Several possible models for TCR engagement of viral superantigen/MHC class II complexes are discussed.
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Clonal deletion
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Abstract Superantigens (SAGs) aberrantly alter immune system function through simultaneous interaction with lateral surfaces of MHC class II molecules on APCs and with particular variable regions of the TCR β-chain (Vβ). To further define the interface between the bacterial SAG toxic shock syndrome toxin-1 (TSST-1) and the TCR, we performed alanine scanning mutagenesis within the putative TCR binding region of TSST-1 along the central α helix adjacent to the N-terminal α helix and the β7-β9 loop as well as with two universally conserved SAG residues (Leu137 and Tyr144 in TSST-1). Mutants were analyzed for multiple functional activities, and various residues appeared to play minor or insignificant roles in the TCR interaction. The locations of six residues (Gly16, Trp116, Glu132, His135, Gln136, and Gln139), each individually critical for functional activity as well as direct interaction with the human TCR Vβ2.1-chain, indicate that the interface occurs in a novel region of the SAG molecule. Based on these data, a model of the MHC/TSST-1/TCR ternary complex predicts similarities seen with other characterized SAGs, although the CDR3 loop of Vβ2.1 is probably involved in direct SAG-TCR molecular interactions, possibly contributing to the TCR Vβ specificity of TSST-1.
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Alanine scanning
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Studies have shown over‐representation of certain T‐cell receptor (TCR) Vβ chains in lesional psoriatic skin, implying selection or expansion, possibly by bacterial superantigen. We investigated the pattern of TCR Vβ chain usage in peripheral blood lymphocytes (PBL) bearing the skin homing receptor cutaneous lymphocyte associated antigen (CLA) in psoriasis patients. Results showed increased expression of TCR Vβ2 in CLA‐positive PBL in psoriasis patients (n = 15) compared with normals (n = 10); P < 0.002. As Vβ2 is preferentially expressed by lymphocytes responding to certain bacterial superantigens, this study could possibly indicate a role for superantigens in the pathogenesis of psoriasis.
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Homing (biology)
Pathogenesis
Lymphocyte homing receptor
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Reactivity of murine T cells with viral or bacterial superantigens is clearly correlated with the expression of TCR V beta domains. Thus, T cells responding to the minor lymphocyte stimulatory locus (Mls-1a) or staphylococcal enterotoxin B (SEB) express predominantly TCR V beta 6 or V beta 8.2 respectively. We have investigated the involvement of the other major variable element of the TCR, the V alpha domain, in these superantigen responses. Using a panel of anti-TCR V alpha mAbs, it is demonstrated that the TCR V alpha repertoire among superantigen stimulated V beta 6+ or V beta 8.2+ blasts (responding to Mls-1a or SEB respectively in vitro) is altered in comparison with anti-CD3 stimulated cells expressing the same V beta domains. Furthermore, the TCR V alpha repertoire is strongly skewed in TCR V beta 8.2 transgenic mice that have undergone extensive peripheral clonal deletion after SEB injection. These data imply that the V alpha domain influences superantigen recognition by the TCR.
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Clonal deletion
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T cell activation by peptide/MHC complexes, superantigens, or mAbs induces the down-regulation of cell surface TCRs. We addressed the question of whether TCR down-modulation affects only TCRs that had directly interacted with their ligand or whether down-modulation could also affect TCRs that had not interacted with their ligand. To this end, we generated T cells coexpressing equal levels of two different TCRs by transfecting the appropriate cDNAs into cells of the human T cell line, Jurkat. Each set of TCRs can be distinguished by means of anti-Vbeta mAbs and can be stimulated separately with peptide Ag, bacterial superantigens, or mAbs. We found that activation of these cells with each of these stimuli down-modulated not only directly stimulated TCR complexes but also unstimulated ones. Comodulation of stimulated and unstimulated receptors may reflect functional interactions between surface TCRs that could take place during Ag or superantigen recognition by T cells without the need for ligand cross-linking. Consistent with this idea, both stimulated and unstimulated receptors colocalized in patches on the cell surface after activation.
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