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

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PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-Versus-Host Disease PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-versus-Host Disease This information is current as Kathryn W. Juchem, Faruk Sacirbegovic, Cuiling Zhang, of October 1, 2021. Arlene H. Sharpe, Kerry Russell, Jennifer M. McNiff, Anthony J. Demetris, Mark J. Shlomchik and Warren D. Shlomchik J Immunol 2018; 200:834-846; Prepublished online 6 December 2017; doi: 10.4049/jimmunol.1701076 Downloaded from http://www.jimmunol.org/content/200/2/834 Supplementary http://www.jimmunol.org/content/suppl/2017/12/05/jimmunol.170107 http://www.jimmunol.org/ Material 6.DCSupplemental References This article cites 50 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/200/2/834.full#ref-list-1 Why The JI? Submit online. by guest on October 1, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-versus-Host Disease Kathryn W. Juchem,*,1 Faruk Sacirbegovic,† Cuiling Zhang,* Arlene H. Sharpe,‡ Kerry Russell,x,2 Jennifer M. McNiff,{,‖ Anthony J. Demetris,# Mark J. Shlomchik,*,**,††,3 and Warren D. Shlomchik*,†,x,††,4 Effector memory T cells (TEM) are less capable of inducing graft-versus-host disease (GVHD) compared with naive T cells (TN). 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 TEM reduced their GVHD potency relative to TS1 TN. Posttransplant, TS1 TEM progeny expressed higher levels of PD-1 than did TS1 TN progeny, leading us to test the hypothesis that TEM induce less GVHD because of increased sensitivity to PD-ligands. In this study, we tested this hypothesis and found that indeed TS1 TEM induced more severe skin and liver GVHD in the absence of PD-ligands. However, lack Downloaded from of PD-ligands did not result in early weight loss and colon GVHD comparable to that induced by TS1 TN, indicating that additional pathways restrain alloreactive TEM. TS1 TN 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 TEM or TN, indicating that donor PD- ligand–expressing APCs critically regulate GVHD. In the absence of PD-ligands, both TS1 TEM and TN 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 http://www.jimmunol.org/ donor APC regulatory function. In summary, PD-ligands suppress both miHA-directed GVHD and the development of alloimmunity-induced autoimmunity after allogeneic hematopoietic transplantation. The Journal of Immunology, 2018, 200: 834–846. llogeneic hematopoietic stem cell transplantation T cells (TEM) fail to induce sustained GVHD, but engraft and can (alloSCT) can cure hematological malignancies and mediate GVL (1–5). These data support the selective depletion of A nonmalignant inherited and acquired disorders of blood TN as a method of GVHD prevention. This has shown promise in cells. Mature allograft abT cells promote engraftment, contribute humans, wherein TN depletion reduced chronic GVHD, without by guest on October 1, 2021 to immune reconstitution, and can attack malignant cells, mediating an apparent increase in risk for relapse (6). Additional efforts to the graft-versus-leukemia (GVL) effect. However, alloreactive T cells understand the mechanisms behind this effect could help to further also attack recipient nonmalignant cells, causing graft-versus-host optimize this approach in humans. disease (GVHD). Because of GVHD, all patients receive some However, why memory T cells (TM) and, in particular, TEM, form of immunosuppression to diminish its incidence and severity. fail to induce GVHD is incompletely understood. Deciphering A primary goal of alloSCT research is to understand and differ- the mechanisms might provide strategies to similarly impair entiate mechanisms of GVHD and GVL to maximize the positive GVHD-inducing TN. We initially considered that TEM may be effects of donor T cells while minimizing GVHD. less capable of causing GVHD because they are relatively re- Toward this end, we and others discovered in mouse models that stricted from key sites of priming such as lymph nodes, but this naive T cells (TN) induce severe GVHD, whereas effector memory proved incorrect (7). To test whether TEM fail to induce GVHD *Department of Immunobiology, Yale University School of Medicine, New This work was supported by National Institutes of Health Grant R01 HL109599. This Haven, CT 06520; †Department of Medicine, University of Pittsburgh, Pitts- work benefited from the use of the special Becton Dickinson LSR Fortessa, funded by burgh, PA 15261; ‡Department of Microbiology and Immunology, Harvard National Institutes of Health Grant 1S10OD011925-01. Medical School, Boston, MA 02115; xDepartment of Medicine, Yale University { K.W.J. designed and performed experiments, analyzed data, and wrote the paper. F.S. School of Medicine, New Haven, CT 06520; Department of Dermatology, Yale ‖ designed and performed experiments and analyzed data. C.Z. performed experiments. University School of Medicine, New Haven, CT 06520; Department of Pathol- 2 2 K.R. interpreted echocardiography results. A.H.S. created the PD-L1/2 / mice. ogy, Yale University School of Medicine, New Haven, CT 06520; #Department J.M.M. and A.J.D. scored histopathology. W.D.S. and M.J.S. conceived the project, of Pathology, University of Pittsburgh, Pittsburgh, PA 15261; **Department of designed experiments, analyzed data, and wrote the paper. Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520; and ††Department of Immunology, University of Pittsburgh, Pittsburgh, Address correspondence and reprint requests to Dr. Warren D. Shlomchik, University PA 15261 of Pittsburgh School of Medicine, Thomas E. Starzl Biomedical Science Tower, Room E1552, 200 Lothrop Street, Pittsburgh, PA 15261. E-mail address: [email protected] 1Current address: Boehringer Ingelheim, Ridgefield, CT. The online version of this article contains supplemental material. 2Current address: Novartis Institute for Biomedical Research, Cambridge, MA. Abbreviations used in this article: alloSCT, allogeneic hematopoietic stem cell trans- 3Current address: Department of Immunology, University of Pittsburgh, Pittsburgh, PA. plantation; BM, bone marrow; GVHD, graft-versus-host disease; GVL, graft-versus- 4 Current address: Department of Medicine, University of Pittsburgh, Pittsburgh, PA. leukemia; HA, hemagglutinin; miHA, minor histocompatibility Ag; TEM, effector memory T cell; TKO, triple knockout; T , memory T cell; T , naive T cell; Treg, ORCID: 0000-0002-1084-6240 (K.R.). M N regulatory T cell; WT, wild type. Received for publication July 28, 2017. Accepted for publication November 3, 2017. Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701076 The Journal of Immunology 835 solely because of their having a less alloreactive TCR repertoire Cell sorting and/or whether repertoire-independent properties also reduce + dim 2 TS1 TN (CD62L CD44 CD25 ) were sorted from unmanipulated TS1 2 + 2 their ability to cause GVHD, we developed a TCR-transgenic mice, and TS1 TEM (CD62L CD44 CD25 ) were sorted from memory mice. GVHD model that enabled direct comparison of TN and TEM To avoid staining cells with anti-CD4 Ab, which we found to reduce en- + + + with identical TCRs. In this model, BALB/c CD4+ TCR- graftment, TS1 cells were enriched via exclusion of CD11b , F4/80 ,CD8a , + + + transgenic T cells (TS1 T cells), specific for the hemagglutinin and CD25 cells. Sorted cells were 40–60% CD4 TS1 ,withnocontaminating CD8+ TS1+ cells. Purities of CD4+ T and T among TS1 cells were .99%. (HA)-derived S1 peptides 110–119 (SFERFEIFPK) presented by N EM I-Ed, were combined with BALB/c bone marrow (BM) and GVHD protocol transferred into irradiated BALB/c recipients that express HA at Seven- to twelve-week-old HA104 BALB/c hosts were irradiated with 750 6 a low level in all cells (HA104 mice) (8). TS1 TN induced severe cGy via a cesium irradiator and transplanted with 8 3 10 BM cells alone or acute GVHD, characterized by weight loss and typical GVHD in combination with 1000 sorted TS1 TN or TEM, except as otherwise pathology of skin, liver, and colon. In contrast, TS1 T induced noted. Recipients received wet food and Sulfatrim-treated water for 2 wk EM posttransplant. Weights were taken two to three times per week. Mice that only transient disease,
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