Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality.

Blood
Dominik SchneidawindRobert S Negrin

Abstract

Graft-versus-host disease (GVHD) is driven by extensive activation and proliferation of alloreactive donor T cells causing significant morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Invariant natural killer T (iNKT) cells are a potent immunoregulatory T-cell subset in both humans and mice. Here, we explored the role of adoptively transferred third-party CD4(+) iNKT cells for protection from lethal GVHD in a murine model of allogeneic HCT across major histocompatibility barriers. We found that low numbers of CD4(+) iNKT cells from third-party mice resulted in a significant survival benefit with retained graft-versus-tumor effects. In vivo expansion of alloreactive T cells was diminished while displaying a T helper cell 2-biased phenotype. Notably, CD4(+) iNKT cells from third-party mice were as protective as CD4(+) iNKT cells from donor mice although third-party CD4(+) iNKT cells were rejected early after allogeneic HCT. Adoptive transfer of third-party CD4(+) iNKT cells resulted in a robust expansion of donor CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) that were required for protection from lethal GVHD. However, in vivo depletion of myeloid-derived suppressor cells abrogated both Tre...Continue Reading

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Citations

Nov 21, 2015·Expert Review of Clinical Immunology·Barbarella LucarelliFranco Locatelli
Jan 19, 2016·Current Stem Cell Reports·Antonio PieriniRobert S Negrin
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Aug 23, 2019·Bone Marrow Transplantation·Robert S Negrin
Apr 5, 2017·Frontiers in Immunology·Sakhila GhimireErnst Holler
Nov 1, 2018·Oncoimmunology·Tereza ComanMarie-Thérèse Rubio
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Jun 12, 2021·Life Science Alliance·Nicholas J HessJenny E Gumperz
Aug 12, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Federico SimonettaRobert S Negrin

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