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Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 and CD8 T Cell-Mediated Alloimmune Responses In Vivo
| Content Provider | Scilit |
|---|---|
| Author | Ito, Toshiro Ueno, Takuya Clarkson, Michael R. Yuan, Xueli Jurewicz, Mollie M. Yagita, Hideo Azuma, Miyuki Sharpe, Arlene H. Auchincloss, Hugh Sayegh, Mohamed H. Najafian, Nader |
| Copyright Year | 2005 |
| Description | Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of $CD4^{−/−}$ but not $CD8^{−/−}$ recipients of BALB/c hearts. The same treatment led to prompt rejection in $CD28^{−/−}$ and a smaller proportion of $CD4^{−/−}CD28^{−/−}$ mice with no effect in $CD8^{−/−}CD28^{−/−}$ recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive $CD8^{+}$ T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in $CD28^{−/−}$ and $CD8^{−/−}CD28^{−/−}$ recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-γ-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance. |
| Ending Page | 6656 |
| Page Count | 9 |
| Starting Page | 6648 |
| ISSN | 00221767 |
| e-ISSN | 15506606 |
| DOI | 10.4049/jimmunol.174.11.6648 |
| Journal | The Journal of Immunology |
| Issue Number | 11 |
| Volume Number | 174 |
| Language | English |
| Publisher | The American Association of Immunologists |
| Publisher Date | 2005-06-01 |
| Access Restriction | Open |
| Subject Keyword | Pathway Can Regulate B7 Pathway Negative Signaling Wild Type Alloreactive T Cells |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
