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International Immunology Advance Access originally published online on March 26, 2009
International Immunology 2009 21(5):567-574; doi:10.1093/intimm/dxp023
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© The Author 2009. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press and The Japanese Society for Immunology are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

T cell sensitivity to TGF-β is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber

Robert E. Cone1,2, Subhasis Chattopadhyay1, Roshanak Sharafieh1, Yen Lemire1, James O'Rourke1,2, Richard A. Flavell3 and Robert B. Clark1,4

1 Department of Immunology
2 Connecticut Lions Vascular Vision Center, University of Connecticut Health Center, Farmington, CT 06030-3105, USA
3 Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, TAC S-569 Box 208011, New Haven, CT 06520-1601, USA
4 Center for Immunotherapy of Cancer and Infectious Diseases and Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030-1601, USA

Correspondence to: R. E. Cone; E-mail: cone{at}uchc.edu

The introduction of antigen into the anterior chamber (AC) of the eye induces the production of antigen-specific splenic CD8+ regulatory T cells (AC-SPL cells) that suppress a delayed-type hypersensitivity (DTH) reaction in immunized mice. Because the generation of these regulatory T cells is also induced by exposure to transforming growth factor (TGF)-β and antigen or F4/80+ cells exposed to TGF-β and antigen in vitro, we investigated (i) whether these cells are produced in dominant negative receptor for transforming growth factor β receptor type II (dnTGFβRII) or Cbl-b–/– mice whose T cells are resistant to TGF-β, (ii) whether DTH is suppressed by wild type (WT) CD8+ AC-SPL cells in Cbl-b–/– and dnTGFβRII mice and (iii) the effect of antibodies to TGF-β on the suppression of DTH by CD8+ AC-SPL cells. DnTGFβRII immunized and Cbl-b–/– mice produced splenic CD8+ regulatory cells after the intracameral injection of antigen and immunization. The suppression of a DTH reaction by CD8+ AC-SPL cells in WT mice was blocked by the local inclusion of antibodies to TGF-β when WT splenic CD8+ AC-SPL cells were injected into the DTH reaction site. Moreover, the DTH reaction in immunized dnTGFβRII and Cbl-b–/– mice was not suppressed by the transfer of WT CD8+ AC-SPL cells to the site challenged with antigen. In aggregate, these observations suggest that T cell sensitivity to TGF-β is not an obligate requirement for the in vivo induction of CD8+ AC-SPL T cells but the suppression of an in vivo DTH reaction by CD8+ AC-SPL cells is dependent on TGF-β.

Keywords: regulatory T cell, TGF-β, tolerance/suppression

Transmitting editor: M. Feldmann

Received 19 November 2008, accepted 14 February 2009.


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