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Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells

Jing Du, Katelyn Paz, Govindarajan Thangavelu, Dominik Schneidawind, Jeanette Baker, Ryan Flynn, Omar Duramad, Colby Feser, Angela Panoskaltsis-Mortari, Robert S. Negrin and Bruce R. Blazar

Key points

  • Low doses of donor iNKT infusion prevents and reverses murine cGVHD.

  • iNKT efficacy in treating established cGVHD is dependent on donor Treg expansion.

Abstract

Chronic graft-versus-host-disease (cGVHD) can cause multi-organ system disease typically with autoimmune-like features, resulting in high mortality and morbidity due to treatment limitations. Invariant natural killer T cells (iNKTs), a small population characterized by expression of a semi-invariant T-cell receptor, rapidly produce copious amounts of diverse cytokines upon activation that exert potent immune regulatory function. Here, we show that iNKTs are significantly reduced in a cGVHD murine model that recapitulates several aspects of autoimmunity and organ fibrosis observed in cGVHD patients. Low iNKT infused doses effectively prevented and, importantly, reversed established cGVHD, as did third-party iNKTs. iNKTs suppressed the autoimmune response by reducing the germinal center (GC) reaction, associated with an increase in total Tregs and follicular Tregs (Tfr) that control the GC reaction along with pathogenic antibody production. Treg depletion during iNKT infusions completely abolished iNKT efficacy in treating cGVHD. iNKT cell IL-4 production and GC migration were critical to cGVHD reversal. In vivo stimulation of iNKT cells by alpha-galactosyl-ceraminde was effective in both preventing and treating cGVHD. Together, this study demonstrates iNKT deficiency in cGVHD mice and highlights the key role of iNKTs in regulating cGVHD pathogenesis and as a potentially novel prophylactic and therapeutic option for cGVHD patients.

  • Submitted November 21, 2016.
  • Accepted April 6, 2017.