Requirement for Interactions of Natural Killer T Cells and Myeloid-Derived Suppressor Cells for Transplantation Tolerance

Abstract

The goal of the study was to elucidate the cellular and molecular mechanisms by which a clinically applicable immune tolerance regimen of combined bone marrow and heart transplants in mice results in mixed chimerism and graft acceptance. The conditioning regimen of lymphoid irradiation and anti-T cell antibodies changed the balance of cells in the lymphoid tissues to create a tolerogenic microenvironment favoring the increase of natural killer T (NKT) cells, CD4+CD25+ Tregs, and Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs), over conventional T cells. The depletion of MDSCs abrogated chimerism and tolerance, and add back of these purified cells was restorative. The conditioning regimen activated the MDSCs as judged by the increased expression of arginase-1, IL-4Rα, and PDL1, and the activated cells gained the capacity to suppress the proliferation of conventional T cells to alloantigens in the mixed leukocyte reaction. MDSC activation was dependent on the presence of host invariant NKT cells. The conditioning regimen polarized the host invariant NKT cells toward IL-4 secretion, and MDSC activation was dependent on IL-4. In conclusion, there was a requirement for MDSCs for chimerism and tolerance, and their suppressive function was dependent on their interactions with NKT cells and IL-4.

Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells

“…Thus, it is likely that these cells also interact with anti-Gr-1 antibodies and L-NMMA. However, administration of anti Gr-1 antibodies (RB6-8C5) or L-NMMA is a commonly used technique to deplete MDSC populations and inhibit MDSC function in vivo (4)(5)(6)8,12,33). Thus, in our experiment, systemic administration of anti-Gr-1 antibodies and L-NMMA was used to examine the extent to which MDSCs contribute to the prolongation of cardiac allograft survival in rapamycin-treated recipients.…”

“…Several studies have examined the relationship between allograft survival and the presence of immune cells by either removing specific cells from the recipient or by adoptively transferring cells into the recipient (1,2). Growing evidence suggests that myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting cancer (3), suppressing autoimmune disease (4) and organ transplant rejection (5)(6)(7)(8). Thus, it would be interesting to examine the mechanisms by which MDSCs suppress immunological rejection and to identify the specific molecules involved; such knowledge could then be applied to clinical organ transplantation.…”

Innate Immune Cell Collaborations Instigate Transplant Tolerance

“…Significantly, the suppressive function of the MDSC requires the influence of IL-4-secreting host iNKT cells. The findings by Hongo et al (9) support an important and powerful tolerogenic mechanism where Th2 cytokines, including IL-4, up-regulate Arg1 in MDSC that block T effector proliferation and promote Treg (Figure 1). Accordingly, these current insights (9) and recent related publications (7,8) (4), it can be speculated that following TLI, ATS and donor bone marrow transplantation, iNKT secreted IL-4 binds to IL-4R on CD11b þ Gr-1 þ MDSC in transplant recipients to support suppression of effector T cell proliferation and expansion CD4 þ CD25 þ Treg through programmed death-ligand 1 (PD-L1) and arginase 1 (Arg1) dependent mechanisms.…”

“…In this issue of the American Journal of Transplantation, Hongo et al provide novel mechanistic insights that link essential IL-4-producing iNKT cells and IL-4 receptor (R)-expressing MDSC for the induction of heart transplant tolerance following a conditioning regimen of TLI, antithymocyte serum (ATS) and donor BMT (9). Specifically, the authors establish that this conditioning regimen generates a tolerogenic environment with augmented numbers of MDSC and iNKT cells that are of critical importance for regulation of alloimmunity.…”

Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants

“…59,66,69 An example of the complex interactions of regulatory cells after conditioning of mice with TLI is shown in Figure 1. Due to the high sensitivity of conventional T cells to radiation-induced cell death, the more radio-resistant CD8 …”