Interleukin-10–mediated regulatory T-cell responses to epitopes on a human red blood cell autoantigen

Hall, Andrew M.; Ward, Frank J.; Vickers, Mark A.; Stott, Lisa-Marie; Urbaniak, S. J.; Barker, Robert N.

doi:10.1182/blood-2002-05-1383

Cited by 70 publications

(117 citation statements)

References 46 publications

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“…However, the results do strongly indicate a tendency for helper responses to be dominated by T cells specific for peptides in particular regions of antigens. Analogous observations have been made in other human systems, including responses to the RhD protein [25][26][27] and for exogenous antigens such as tetanus and diphtheria toxoid-based vaccines, where commonly targeted regions of antigens have been termed universal epitopes. 28 Accessibility of particular regions of the antigen during processing has been suggested as a structural …”

Section: Discussionmentioning

confidence: 87%

Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells

Zou

Hannier

Cairns

et al. 2008

Journal of the American Society of Nephrology

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Autoreactive T cells in patients with Goodpasture's disease are specific for epitopes in the Goodpasture antigen (the NC1 domain of the ␣3 chain of type IV collagen) that are rapidly destroyed during antigen processing to a degree that diminishes their presentation to T cells. We hypothesized that patients' autoreactive T cells exist because antigen processing prevents presentation of the self-epitopes they recognize, circumventing specific tolerance mechanisms. We predicted that autoreactive T cells specific for these peptides should also exist in healthy individuals, albeit at low frequency and in an unprimed state. We obtained blood from healthy unrelated donors and, using a panel of 45 ␣3(IV)NC1 peptides, identified ␣3(IV)NC1-specific T cells in all donors. Thirty-six of 45 peptides elicited a proliferative T cell response from at least one subject, and 6 of the peptides evoked a response in Ͼ50% of the individuals. This consistency was not caused by selectivity of HLA class II molecules because the donors expressed a diversity of HLA antigens, but was largely a result of the substrate-specificity of the endosomal proteases Cathepsin D and E. There was a significant correlation between high susceptibility to Cathepsin D digestion and the capacity to stimulate primary T cell responses (P ϭ 0.00006). In summary, healthy individuals have low frequencies of unstimulated ␣3(IV)NC1-reactive T cells with similar specificities to the autoreactive T cells found in patients with Goodpasture disease. In both cases, existence of the ␣3(IV)NC1-reactive T cells can be accounted for by destructive processing.

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Section: Discussionmentioning

confidence: 87%

Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells

Zou

Hannier

Cairns

et al. 2008

Journal of the American Society of Nephrology

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“…The Grampian Health Board and the University of Aberdeen Ethical Committee approved investigation protocols. PBMCs were prepared and cultured essentially as previously described [50] in RPMI 1640 medium (Invitrogen, Paisley, UK) supplemented with 5% autologous human serum in an atmosphere of 37 • C, 5% CO 2 . Unless stated otherwise, 1 × 10 6 PBMCs were cultured for 5 days in 1 mL wells.…”

Section: Donors and Sample Preparationmentioning

confidence: 99%

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

et al. 2013

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CTLA-4 is a crucial immune regulator that mediates both negative costimulation signals to T cells, and regulatory T (Treg)-cell extrinsic control of effector responses.Here we present evidence supporting a novel mechanism for this extrinsic suppression, executed by the alternatively spliced soluble CTLA-4 isoform (sCTLA-4). Analyses of human T cells in vitro show that sCTLA-4 secretion can be increased during responses, and has potent inhibitory properties, since isoform-specific blockade of its activity significantly increased Ag-driven proliferation and cytokine (IFN-γ, IL-17) secretion. Treg cells were demonstrated to be a prominent source of sCTLA-4, which contributed to suppression in vitro when their numbers were limiting. The soluble isoform was also produced by, and inhibited, murine T cells responding to Ag in vitro, and blockade of its activity in vivo protected against metastatic spread of melanoma in mice. We conclude that sCTLA-4 is an important immune regulator, responsible for at least some of the inhibitory effects previously ascribed to the membrane-bound isoform. These results suggest that the immune system exploits the different CTLA-4 isoforms for either intrinsic or extrinsic regulation of T-cell activity. Keywords: CD4 + T cells r Costimulatory molecules r Immune regulation r Treg cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site Introduction CTLA-4 is an important regulator of T-cell responses [1][2][3][4]. Its critical role is highlighted by CTLA-4 knockout mice, which develop a fatal lymphoproliferative disorder soon after birth, arising from a profound failure of T-cell homeostasis [5,6]. Despite these potent effects, the activities of CTLA-4 are only partially understood.CTLA-4 shares sequence homology and B7 ligands (CD80/CD86) with the costimulatory molecule, CD28, but differs by delivering inhibitory, rather than activating, signals to the T cells on which it is expressed as a receptor [7,8]. Upregulation of CTLA-4 on activated T cells provides a mechanism for negative Correspondence: Dr. Frank J. Ward e-mail: mmd475@abdn.ac.uk feedback to control their responses. However, not all its regulatory effects are explained by inhibitory costimulation, since CTLA-4 can also suppress activated effector T-cell populations without the need for them to express it [9,10]. This latter, cell-extrinsic mechanism has been largely attributed to CD4 + regulatory T (Treg)-cell subsets, which constitutively express high levels of CTLA-4, and require it for their regulatory function [11][12][13][14][15][16].How Treg cells might use CTLA-4 to regulate effector T-cell responses remains controversial. It has been suggested that CTLA-4 on Treg cells binds B7 and thus blocks CD28-mediated effector T-cell costimulation, or that it induces inhibitory mechanisms in the APC such as the IDO tryptophan catabolic enzyme * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1274-1285 Immunomodulation 1275 cas...

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“…13,[19][20][21] The proliferation by the cells was recorded as mean cpm Ϯ SD of the triplicate samples, or as a stimulation index (SI) expressing the rate of mean cpm in stimulated versus unstimulated control cultures. An SI Ͼ 3 was interpreted as a proliferative response.…”

Section: T-cell Proliferation Assaymentioning

confidence: 99%

“…The viability of the PBMCs was Ͼ 90%, as confirmed by trypan blue staining. As previously described, 13,[19][20][21] PBMCs were cultured at a final concentration of 1.25 ϫ 10 6 cells/mL in ␣ modification of Eagle medium (␣-MEM; Invitrogen) supplemented with 1% 2mM L-glutamine (Invitrogen), 2% 20mM HEPES buffer (Sigma-Aldrich), 2% penicillin streptomycin (Invitrogen), and 5% autologous sera. PBMCs were incubated with peptides or control stimuli for 5 days at 37°C in a humidified atmosphere of 5% CO 2 /95% air.…”

Section: Isolation and Culture Of Pbmcsmentioning

confidence: 99%