A Signal Peptide Derived from hsp60 Binds HLA-E and Interferes with CD94/NKG2A Recognition

Michaëlsson, Jakob; Matos, Cristina Teixeira de; Achour, Adnane; Lanier, Lewis L.; Kärre, Klas; Söderström, Kalle

doi:10.1084/jem.20020797

Cited by 236 publications

(219 citation statements)

References 50 publications

(70 reference statements)

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“…This implies that the NKG2A ligand HLA-E, but not the KIR ligand HLA-C, is down-regulated in this system. Hsp60 has a leader sequence that binds HLA-E but is not permissive for recognition by NKG2A (40). However, we did not observe a change in the levels of hsp60 by Western blot (not shown).…”

Section: Vaccinia Virus Infection Induces Down-regulation Of Hla-ementioning

confidence: 44%

The Inhibitory Receptor NKG2A Determines Lysis of Vaccinia Virus-Infected Autologous Targets by NK Cells

Brooks

Elliott

Parham

et al. 2006

The Journal of Immunology

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Signals transduced by inhibitory receptors that recognize self-MHC class I molecules prevent NK cells from being activated by autologous healthy target cells. In order for NK cells to be activated upon contact with an infected cell, the balance between the activating and inhibitory signals that regulate NK cell function must be altered in favor of activation. By studying liver-derived NK cells, we show that only a subpopulation of NK cells expressing high levels of the inhibitory receptor NKG2A are able to lyse autologous vaccinia-infected targets, and that this is due to selective down-regulation of HLA-E. These data demonstrate that release from an inhibitory receptor:ligand interaction is one mechanism that permits NK cell recognition of a virally infected target, and that the variegated expression of inhibitory receptors in humans generates a repertoire of NK cells with different antiviral potentials.

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Section: Vaccinia Virus Infection Induces Down-regulation Of Hla-ementioning

confidence: 44%

The Inhibitory Receptor NKG2A Determines Lysis of Vaccinia Virus-Infected Autologous Targets by NK Cells

Brooks

Elliott

Parham

et al. 2006

The Journal of Immunology

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“…However, Qa-1 can also bind other selfpeptides, including those derived from heat shock proteins (15) and preproinsulin leader sequences (16). In addition, human studies have shown that a signal peptide derived from the leader sequence of a stress protein Hsp60 (Hsp60sp) is capable of competing with the B7sp peptide, the human counterpart of Qdm, for occupancy of HLA-E, the human counterpart of Qa-1 (17). Interestingly, the resultant HLA-E/Hsp60sp complex does not interact with CD94/ NKG2A and therefore does not inhibit the NK activity.…”

Section: Resultsmentioning

confidence: 99%

Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation

Chen

Zhang

Liang

et al. 2007

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

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The structure recognized by regulatory T cells that enables them to discriminate self from nonself in the periphery is one of the central issues of regulatory T cell biology. A link between immunoregulation and self-nonself discrimination has emerged from experiments showing that Qa-1-restricted CD8 ؉ T cells selectively downregulate target T cells activated by the intermediate avidity of their own T cell antigen receptor-ligand interactions. Because the peripheral self-reactive T cell repertoire is devoid of high-avidity T cells compared with the foreign-reactive repertoire, as a result of thymic negative selection, the selective down-regulation of intermediate but not high-avidity T cells enables the immune system to suppress autoimmunity without damaging the ongoing immune response to foreign pathogens. However, the molecular mechanism delineating how avidity of T cell activation is perceived by the regulatory T cells has not been elucidated. Here we show that a heat shock peptide (Hsp60sp), coupled with the MHC class Ib molecule Qa-1, is a surrogate target structure that is preferentially expressed at a higher level on the intermediate avidity T cells and specifically recognized by the Qa-1-restricted CD8 ؉ T cells. The biological significance of this observation was confirmed by the ability of Hsp60sp-loaded relevant dendritic cells to induce a Qa-1-restricted CD8 ؉ T cell-mediated protection from autoimmune encephalopathy in the experimental allergic encephalomyelitis model. Thus, perceiving the avidity of T cell activation can be translated into peripheral T cell regulation to discriminate self from nonself in the periphery to maintain self-tolerance.autoimmune diseases ͉ Qa-1/HLA-E-restricted regulatory CD8 ϩ T cells ͉ self-nonself discrimination H ow the immune system achieves self-nonself discrimination remains a central conundrum in the study of immunology. Intrathymic deletion of high-avidity, self-reactive T cell clones generates a truncated peripheral self-reactive repertoire composed of mainly intermediate-and low-but devoid of high-avidity clones compared with the foreign-reactive repertoire, which possesses T cells with a full range of avidity. It is likely that potentially pathogenic self-reactive T cells are included in the pool of the ''intermediate-avidity'' thymic escapees that could be activated in the periphery to initiate autoimmune diseases (1-4). It is thus inevitable that one of the major functions of peripheral regulatory mechanisms is to selectively down-regulate immune response to self-antigens without damaging the ongoing immune response to foreign pathogens (5). The distinctive composition of peripheral T cell repertoires to self vs. to foreign antigens provides a unique opportunity for the immune system to discriminate self from nonself in the periphery by a unified mechanism of selectively down-regulating intermediate-avidity T cells to both self and foreign antigens. Selective down-regulation of intermediate-avidity T cell populations containing the potentially pathogenic self...

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“…21 In addition, HSPs can induce a polyclonal immune response and activate NK cells. 22,23 Thus, HSPbased vaccines emerge as promising strategy for immunotherapy. Accordingly, vaccination with autologous tumor-derived HSP-peptide complexes has been shown to result in both prophylactic and therapeutic antitumoral activity in a variety of animal models of cancer and several advanced clinical studies using autologous tumorderived HSPs are underway.…”

Section: Introductionmentioning

confidence: 99%

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

et al. 2008

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Considering that mycobacterial heat-shock protein 65 (hsp65) gene transfer can elicit a profound antitumoral effect, this study aimed to establish the safety, maximum-tolerated dose (MTD) and preliminary efficacy of DNA-hsp65 immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). For this purpose, 21 patients with unresectable and recurrent HNSCC were studied. Each patient received three ultrasound-guided injections at 21-day intervals of: 150, 600 or 400 mg of DNA-hsp65. Toxicity was graded according to CTCAE directions. Tumor volume was measured before and after treatment using computed tomography scan. The evaluation included tumor mass variation, delayed-type hypersensitivity response and spontaneous peripheral blood mononuclear cell proliferation before and after treatment. The MTD was 400 mg per dose. DNAhsp65 immunotherapy was well tolerated with moderate pain, edema and infections as the most frequent adverse effects. None of the patients showed clinical or laboratory alterations compatible with autoimmune reactions. Partial response was observed in 4 out of 14 patients who completed treatment, 2 of which are still alive more than 3 years after the completion of the trial. Therefore, DNA-hsp65 immunotherapy is a feasible and safe approach at the dose of 400 mg per injection in patients with HNSCC refractory to standard treatment. Further studies in a larger number of patients are needed to confirm the efficacy of this novel strategy.

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A Signal Peptide Derived from hsp60 Binds HLA-E and Interferes with CD94/NKG2A Recognition

Cited by 236 publications

References 50 publications

The Inhibitory Receptor NKG2A Determines Lysis of Vaccinia Virus-Infected Autologous Targets by NK Cells

The Inhibitory Receptor NKG2A Determines Lysis of Vaccinia Virus-Infected Autologous Targets by NK Cells

Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

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