Abstract
Invariant natural killer T (iNKT) cells serve as a bridge between innate and adaptive immunity and have been shown to play an important role in immune regulation, defense against pathogens, and cancer immunity. Recent data also suggest that this compartment of the immune system plays a significant role in reducing graft-versus-host disease (GVHD) in the setting of allogeneic hematopoietic stem cell transplantation. Murine studies have shown that boosting iNKT numbers through certain conditioning regimens or adoptive transfer leads to suppression of acute or chronic GVHD. Preclinical work reveals that iNKT cells exert their suppressive function by expanding regulatory T cells in vivo, though the exact mechanism by which this occurs has yet to be fully elucidated. Human studies have demonstrated that a higher number of iNKT cells in the graft or in the peripheral blood of the recipient post-transplantation are associated with a reduction in GVHD risk, importantly without a loss of graft-versus-tumor effect. In two separate analyses of many immune cell subsets in allogeneic grafts, iNKT cell dose was the only parameter associated with a significant improvement in GVHD or in GVHD-free progression-free survival. Failure to reconstitute iNKT cells following allogeneic transplantation has also been associated with an increased risk of relapse. These data demonstrate that iNKT cells hold promise for future clinical application in the prevention of GVHD in allogeneic stem cell transplantation and warrant further study of the immunoregulatory functions of iNKT cells in this setting.
Highlights
Hematopoietic cell transplantation (HCT) remains the only curative treatment option for patients with many hematologic malignancies and hematologic disorders
As demonstrated in the aforementioned murine and human studies, invariant natural killer T (iNKT) cells may be the holy grail sought in stem cell transplantation that is capable both of suppressing allogeneic immune reactions (GVHD) and enhancing anti-tumor immune reactions (GVT)
The murine studies all demonstrated a strong benefit of iNKT cells on graftversus-host disease (GVHD) reduction
Summary
Hematopoietic cell transplantation (HCT) remains the only curative treatment option for patients with many hematologic malignancies and hematologic disorders. Invariant natural killer T cells are a rare subset of T lymphocytes which are characterized by the coexpression of natural killer and T cell markers They express a T cell receptor (TCR) which is semi-invariant (Vα14Jα18 pairing with a limited selection of beta chains in mice and Vα24Jα18 typically pairing with Vβ11 in humans) and which recognizes glycolipid antigens presented by the non-polymorphic MHC Class I-like molecule CD1d with high affinity [3]. Despite their rarity, iNKT cells exert potent immunomodulatory functions bridging the innate and adaptive immune systems by rapidly producing vast amounts of cytokines and chemokines. This results either in enhanced immune responses (i.e., defense against pathogens, immunosurveillance in cancer) via the production of Th1 cytokines such as interferon (IFN)-γ or in suppression of autoimmune and alloimmune reactions by the production of interleukin (IL)-4 and IL-10 [4, 5] (Figure 1)
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