Page 85 - 2022_02-Haematologica-web

Cell Therapy & Immunotherapy
Human invariant natural killer T cells promote tolerance by preferential apoptosis induction of conventional dendritic cells
Hannes Schmid,1* Emmanuelle M. Ribeiro,1* Kathy-Ann Secker,1
Silke Duerr-Stoerzer,1 Hildegard Keppeler,1 Ruoyun Dong,1 Timo Munz,1 Klaus Schulze-Osthoff,2 Stephan Hailfinger,2 Corina Schneidawind1
and Dominik Schneidawind1
1Department of Medicine II, University Hospital Tübingen, Eberhard Karls University, and 2Interfaculty Institute of Biochemistry, Eberhard Karls University, Tübingen, Germany
*HS and EMR contributed equally as co-first authors.
ABSTRACT
Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. We recently showed in murine studies and in vitro human models that adoptively transferred invariant natural killer T (iNKT) cells protect from GvHD and promote graft-versus-leukemia effects. The cellular mechanisms underlying GvHD prevention by iNKT cells in humans, however, remain unknown. In order to study relevant cellular interactions, dendritic cells (DC) were either generated from monocytes or isolated directly from blood of healthy donors or GvHD patients and co-cultured in a mixed lymphocyte reaction (MLR) with T cells obtained from healthy donors or transplantation bags. Addition of culture-expanded iNKT cells to the MLR-induced DC apop- tosis in a cell contact-dependent manner, thereby preventing T-cell activation and proliferation. Annexin V/propidium iodide staining and image stream assays showed that CD4+CD8–, CD4–CD8+ and double negative iNKT cells are similarly able to induce DC apoptosis. Further MLR assays revealed that conventional DC (cDC) but not plasmacytoid DC (pDC) could induce allore- active T-cell activation and proliferation. Interestingly, cDC were also more susceptible to apoptosis induced by iNKT cells, which correlates with their higher CD1d expression, leading to a bias in favor of pDC. Remarkably, these results could also be observed in GvHD patients. We propose a new mecha- nism how ex vivo expanded human iNKT cells prevent alloreactivity of T cells. iNKT cells modulate T-cell responses by selective apoptosis of DC subsets, resulting in suppression of T-cell activation and proliferation while enabling beneficial immune responses through pDC.
Introduction
Despite significant advances in the field of allogeneic hematopoietic cell trans- plantation (HCT), graft-versus-host disease (GvHD) still represents a major compli- cation after allogeneic HCT, leading to substantial morbidity and mortality.1,2 GvHD is mediated by donor T cells activated through antigen-presenting cells (APC).3 Dendritic cells (DC) are professional APC that precisely orchestrate adap- tive immune responses and their significant role in GvHD pathophysiology has been established previously.4-6 Both donor and host DC present host antigens and promote activation and proliferation of alloreactive donor T cells, which conse- quently home to GvHD target sites, resulting in tissue destruction and clinical man- ifestations of GvHD.7,8 The ability of DC to elicit or prevent T-cell responses is tuned by the concomitant expression of stimulatory or inhibitory molecules as well as immunomodulatory cytokines.9
DC also express antigen-presenting molecules such as the major histocompatibil- ity complex-I (MHC-I)-like molecule CD1d that allows for interactions with invari- ant natural killer T (iNKT) cells. iNKT cells are a small subset of T lymphocytes characterized by the expression of an invariant T-cell receptor in both humans and
Ferrata Storti Foundation
Haematologica 2022 Volume 107(2):427-436
Correspondence:
DOMINIK SCHNEIDAWIND
dominik.schneidawind@med.uni-tuebingen.de
Received: July 22, 2020. Accepted: December 22, 2020. Pre-published: January 14, 2021.
https://doi.org/10.3324/haematol.2020.267583 ©2022 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2022; 107(2)
427
ARTICLE