INKT cells coordinate immune pathways to enable engraftment in nonconditioned hosts.

Nicholas J Hess,Nikhila S Bharadwaj,Amy W Hudson,John-Demian Sauer,Jenny E Gumperz,Courtney E Mcdougal,Shidong Ma,Elizabeth A Bobeck

doi:10.26508/lsa.202000999

Nicholas J Hess, Nikhila S Bharadwaj + Show 6 more

Open Access

https://doi.org/10.26508/lsa.202000999

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Abstract

Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that interact with key antigen-presenting cells to modulate adaptive T-cell responses in ways that can either promote protective immunity, or limit pathological immune activation. Understanding the immunological networks engaged by iNKT cells to mediate these opposing functions is a key pre-requisite to effectively using iNKT cells for therapeutic applications. Using a human umbilical cord blood xenotransplantation model, we show here that co-transplanted allogeneic CD4+ iNKT cells interact with monocytes and T cells in the graft to coordinate pro-hematopoietic and immunoregulatory pathways. The nexus of iNKT cells, monocytes, and cord blood T cells led to the release of cytokines (IL-3, GM-CSF) that enhance hematopoietic stem and progenitor cell activity, and concurrently induced PGE2-mediated suppression of T-cell inflammatory responses that limit hematopoietic stem and progenitor cell engraftment. This resulted in successful long-term hematopoietic engraftment without pretransplant conditioning, including multi-lineage human chimerism and colonization of the spleen by antibody-producing human B cells. These results highlight the potential for using iNKT cellular immunotherapy to improve rates of hematopoietic engraftment independently of pretransplant conditioning.

Highlights

Hematopoietic stem cell transplantation (HSCT) is used clinically to treat a variety of malignancies and nonmalignant hematologic diseases such as immunodeficiency disorders (Juric et al, 2016)
The human immune compartment contained a CD34+ subset comprising multiple sub-populations, including multi-potent progenitors (CD38−CD45RA−), committed progenitors (CD38+CD45RA+), myeloid progenitors (CD33+ or CD123+), and early B lymphocytic lineage cells (CD19+) (Fig 1A, top row, middle and right panels). These results indicated that consistent with prior analyses (Cosgun et al, 2014; McIntosh et al, 2015; Yurino et al, 2016; Czechowicz et al, 2019; Hess et al, 2020b), transplanting human cord blood hematopoietic stem and progenitor cells (HSPCs) into nonconditioned NBSGW mice resulted in successful hematopoietic engraftment that was sustained for at least 3 mo
We investigated transplantation of total human umbilical cord blood mononuclear cells (CBMCs) into nonconditioned NSG mice

Summary

Introduction

Hematopoietic stem cell transplantation (HSCT) is used clinically to treat a variety of malignancies and nonmalignant hematologic diseases such as immunodeficiency disorders (Juric et al, 2016). Despite advances in pretransplant conditioning regimens, which are used to reduce tumor burden and ablate host immune cells to facilitate engraftment of transplanted hematopoietic stem and progenitor cells (HSPCs), adverse outcomes including graft failure, graft-versus-host disease (GVHD), and cancer relapse or progression remain highly problematic (Bishop et al, 2011; Tsai et al, 2016; Chen et al, 2017; Yang et al, 2017). Prior studies have focused on the therapeutic potential of iNKT cells for preventing GVHD and promoting GVT after HSCT (Schneidawind et al, 2013; Mavers et al, 2017; Negrin, 2019). Their therapeutic potential for promoting engraftment success remains poorly understood

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