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Blood, 1 May 2002, Vol. 99, No. 9, pp. 3326-3334
IMMUNOBIOLOGY
Heavy chain ferritin activates regulatory T cells by induction of
changes in dendritic cells
Christian P. Gray,
Paolo Arosio, and
Peter Hersey
From the Deparment of Oncology and Immunology,
Newcastle Mater Hospital, Australia; and Section of Chemistry,
Faculty of Medicine, University of Brescia, Italy.
Heavy chain ferritin (H-ferritin) is a component of the
iron-binding protein, ferritin. We have previously shown that
H-ferritin inhibits anti-CD3-stimulated lymphocyte proliferation and
that this was due to increased production of interleukin-10 (IL-10). In
the present study we have shown that induction of IL-10 production was
due to effects of H-ferritin on adherent antigen-presenting cells
(APCs) in blood and monocyte-derived dendritic cells (MoDCs). IL-10 was
produced by a subpopulation of CD4 T cells, which expressed the CD25
component of the IL-2 receptor and the CTLA-4 receptor characteristic
of regulatory T cells. The changes induced in MoDCs were compared with
those induced by CD40L and their significance tested by inhibition with
monoclonal antibodies. These studies indicated that H-ferritin induced
relatively greater expression of CD86 and B7-H1 on MoDCs and that
monoclonal antibodies against their receptors, CTLA-4 and programmed
death receptor-1 (PD-1), inhibited IL-10 production from the regulatory
T cells. H-ferritin did not appear to induce direct production
of the cytokines IL-2, IL-4, IL-6, IL-10, IL-12, or interferon- from
the DCs. These results are consistent with the thesis that H-ferritin
induces B7-H1 and CD86 (B7-2) on APCs, which in turn induce IL-10
production from regulatory T cells. This is possibly one mechanism by
which melanoma cells may induce changes in APCs in the
vicinity of the tumor and result in suppression of immune
responses by induction of regulatory T cells.
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