GSBS Student Publications

Title

TLR agonists abrogate costimulation blockade-induced prolongation of skin allografts

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Medicine, Division of Diabetes; Department of Pathology

Date

1-21-2006

Document Type

Article

Medical Subject Headings

Animals; Antibodies, Monoclonal; Apoptosis; CD40 Ligand; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Clonal Deletion; Female; *Graft Enhancement, Immunologic; Graft Rejection; Growth Inhibitors; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Transgenic; Radiation Chimera; Receptors, Interleukin; Receptors, Interleukin-12; Receptors, Tumor Necrosis Factor, Type II; Skin Transplantation; Toll-Like Receptor 4; Toll-Like Receptors; Transplantation, Homologous

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Costimulation blockade protocols are effective in prolonging allograft survival in animal models and are entering clinical trials, but how environmental perturbants affect graft survival remains largely unstudied. We used a costimulation blockade protocol consisting of a donor-specific transfusion and anti-CD154 mAb to address this question. We observed that lymphocytic choriomeningitis virus infection at the time of donor-specific transfusion and anti-CD154 mAb shortens allograft survival. Lymphocytic choriomeningitis virus 1) activates innate immunity, 2) induces allo-cross-reactive T cells, and 3) generates virus-specific responses, all of which may adversely affect allograft survival. To investigate the role of innate immunity, mice given costimulation blockade and skin allografts were coinjected with TLR2 (Pam3Cys), TLR3 (polyinosinic:polycytidylic acid), TLR4 (LPS), or TLR9 (CpG) agonists. Costimulation blockade prolonged skin allograft survival that was shortened after coinjection by TLR agonists. To investigate underlying mechanisms, we used "synchimeric" mice which circulate trace populations of anti-H2b transgenic alloreactive CD8+ T cells. In synchimeric mice treated with costimulation blockade, coadministration of all four TLR agonists prevented deletion of alloreactive CD8+ T cells and shortened skin allograft survival. These alloreactive CD8+ T cells 1) expressed the proliferation marker Ki-67, 2) up-regulated CD44, and 3) failed to undergo apoptosis. B6.TNFR2-/- and B6.IL-12R-/- mice treated with costimulation blockade plus LPS also exhibited short skin allograft survival whereas similarly treated B6.CD8alpha-/- and TLR4-/- mice exhibited prolonged allograft survival. We conclude that TLR signaling abrogates the effects of costimulation blockade by preventing alloreactive CD8+ T cell apoptosis through a mechanism not dependent on TNFR2 or IL-12R signaling.

Rights and Permissions

Citation: J Immunol. 2006 Feb 1;176(3):1561-70.

Related Resources

Link to Article in PubMed

Journal Title

Journal of immunology (Baltimore, Md. : 1950)

PubMed ID

16424185