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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-05-1383.
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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4529-4536
IMMUNOBIOLOGY
Interleukin-10-mediated regulatory T-cell responses to
epitopes on a human red blood cell autoantigen
Andrew M. Hall,
Frank J. Ward,
Mark A. Vickers,
Lisa-Marie Stott,
Stanislaw J. Urbaniak, and
Robert N. Barker
From the Department of Medicine and Therapeutics,
Institute of Medical Sciences, University of Aberdeen Foresterhill,
Aberdeen, United Kingdom; and the Academic Transfusion
Medicine Unit, Regional Transfusion Centre, Foresterhill, Aberdeen,
United Kingdom.
Regulatory T cells have been shown to control animal models of
immune-mediated pathology by inhibitory cytokine production, but
little is known about such cells in human disease. Here we characterize
regulatory T-cell responses specific for a human red blood cell
autoantigen in patients with warm-type autoimmune hemolytic anemia.
Peripheral blood mononuclear cells from patients with
autoimmune hemolytic anemia were found either to proliferate and produce interferon- or to secrete the regulatory cytokine interleukin 10 when stimulated in vitro with a major red blood cell
autoantigen, the RhD protein. Flow cytometric analysis confirmed that
the majority of the responding cells were of the CD4+
phenotype. Serial results from individual patients demonstrated that this bias toward proliferative or interleukin-10 responses was unstable over time and could reverse in subsequent samples. Epitope
mapping studies identified peptides from the sequence of the
autoantigen that preferentially induced interleukin-10 production, rather than proliferation, and demonstrated that many contain naturally processed epitopes. Responses to such peptides suppressed T-cell proliferation against the RhD protein, an inhibition that was mediated largely by interleukin 10 and dependent on cytotonic T lymphocyte-associated antigen (CTLA-4) costimulation.
Antigenic peptides with the ability to stimulate specific regulatory
cells may represent a new class of therapeutic agents for
immune-mediated disease.
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