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International Immunology Advance Access originally published online on September 11, 2006
International Immunology 2006 18(11):1549-1562; doi:10.1093/intimm/dxl088
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

TCR transgenic CD8+ T cells activated in the presence of TGFß express FoxP3 and mediate linked suppression of primary immune responses and cardiac allograft rejection

Judith A. Kapp1,2, Kazuhito Honjo2, Linda M. Kapp1, Xiao yan Xu2, Alana Cozier2 and R. Pat Bucy2

1 Department of Ophthalmology, Spain Wallace Building, 619 South 19th Street, University of Alabama at Birmingham, Birmingham, AL 35233-7331, USA
2 Department of Pathology, Spain Wallace Building, 619 South 19th Street, University of Alabama at Birmingham, Birmingham, AL 35233-7331, USA

Correspondence to: J. A. Kapp; E-mail: jkapp{at}uab.edu

Although CD4+CD25+FoxP3+ regulatory T cells play a role in allograft tolerance, the role of CD8+ cells with immunosuppressive function is less clear. To address this issue, spleen cells from Rag-1-deficient TCR transgenic (Tg) mice expressing a receptor for ovalbumin (OVA) in the context of MHC class I (OT1) were activated with OVA expressing antigen-presenting cell (APC) in the presence or absence of exogenous transforming growth factor ß (TGFß). TGFß inhibited the expression of IFN-{gamma}, granzyme B and the lytic activity of the OT1 T cells while inducing FoxP3 expression in 5–15% of the cells. By contrast, FoxP3 expression was not detected in naive OT-1 T cells or OT-1 T cells activated without exogenous TGFß. TGFß-activated OT1 cells inhibited the activation of Kd-specific CD8+ CTL responses by normal B6 T cells and the proliferation by Kd-specific CD4+ TCR Tg T cells, but only if the OVA epitope was co-expressed by Kd+ APC. This antigen-specific inhibitory activity, referred to as linked suppression, was neither mediated by residual lytic activity within the activated OT1 T cells nor did it depend upon IL-10 or TGFß. Suppression correlated with inhibition of CD86 expression on CD11c+ APC. TGFß-activated OT1 T cells also delayed the rejection of heterotopic, vascularized cardiac allografts mediated by anti-Kd-specific CD4+ TCR Tg T cells, but only if the cardiac allograft expressed both OVA and Kd as transgenes. Prolonged survival of allografts was associated with rapid migration of the FoxP3+ OT1 T cells into the donor heart raising the possibility that suppression may be mediated within the allograft. These data show that TGFß-activated CD8+ T cells mediate antigen-specific, APC-focused patterns of suppression in vitro and in vivo.

Keywords: CTL, transgenic/knockout mice, transplantation

Transmitting editor: K. Okumura


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