PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-versus-Host Disease.

Autor: Juchem KW; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520., Sacirbegovic F; Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261., Zhang C; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520., Sharpe AH; Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115., Russell K; Department of Medicine, Yale University School of Medicine, New Haven, CT 06520., McNiff JM; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520.; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520., Demetris AJ; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261., Shlomchik MJ; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520; and.; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261., Shlomchik WD; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; warrens@pitt.edu.; Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.; Department of Medicine, Yale University School of Medicine, New Haven, CT 06520.; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261.
Jazyk: angličtina
Zdroj: Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2018 Jan 15; Vol. 200 (2), pp. 834-846. Date of Electronic Publication: 2017 Dec 06.
DOI: 10.4049/jimmunol.1701076
Abstrakt: Effector memory T cells (T EM ) are less capable of inducing graft-versus-host disease (GVHD) compared with naive T cells (T N ). Previously, in the TS1 TCR transgenic model of GVHD, wherein TS1 CD4 cells specific for a model minor histocompatibility Ag (miHA) induce GVHD in miHA-positive recipients, we found that cell-intrinsic properties of TS1 T EM reduced their GVHD potency relative to TS1 T N Posttransplant, TS1 T EM progeny expressed higher levels of PD-1 than did TS1 T N progeny, leading us to test the hypothesis that T EM induce less GVHD because of increased sensitivity to PD-ligands. In this study, we tested this hypothesis and found that indeed TS1 T EM induced more severe skin and liver GVHD in the absence of PD-ligands. However, lack of PD-ligands did not result in early weight loss and colon GVHD comparable to that induced by TS1 T N , indicating that additional pathways restrain alloreactive T EM TS1 T N also caused more severe GVHD without PD-ligands. The absence of PD-ligands on donor bone marrow was sufficient to augment GVHD caused by either T EM or T N , indicating that donor PD-ligand-expressing APCs critically regulate GVHD. In the absence of PD-ligands, both TS1 T EM and T N induced late-onset myocarditis. Surprisingly, this was an autoimmune manifestation, because its development required non-TS1 polyclonal CD8 + T cells. Myocarditis development also required donor bone marrow to be PD-ligand deficient, demonstrating the importance of donor APC regulatory function. In summary, PD-ligands suppress both miHA-directed GVHD and the development of alloimmunity-induced autoimmunity after allogeneic hematopoietic transplantation.
(Copyright © 2018 by The American Association of Immunologists, Inc.)
Databáze: MEDLINE
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