Journal
INTERNATIONAL IMMUNOLOGY
Volume 18, Issue 11, Pages 1549-1562Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxl088
Keywords
CTL; transgenic/knockout mice; transplantation
Categories
Funding
- NEI NIH HHS [EY014877] Funding Source: Medline
- NHLBI NIH HHS [HL50724] Funding Source: Medline
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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 beta (TGF beta). TGF beta 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 TGF beta. TGF beta-activated OT1 cells inhibited the activation of K-d-specific CD8+ CTL responses by normal B6 T cells and the proliferation by K-d-specific CD4+ TCR Tg T cells, but only if the OVA epitope was co-expressed by K-d+ 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 TGF beta. Suppression correlated with inhibition of CD86 expression on CD11c+ APC. TGF beta-activated OT1 T cells also delayed the rejection of heterotopic, vascularized cardiac allografts mediated by anti-K-d-specific CD4+ TCR Tg T cells, but only if the cardiac allograft expressed both OVA and K-d 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 TGF beta-activated CD8+ T cells mediate antigen-specific, APC-focused patterns of suppression in vitro and in vivo.
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