期刊
LIFE SCIENCE ALLIANCE
卷 4, 期 7, 页码 -出版社
LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.202000999
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资金
- National Institutes of Health (NIH) [T32 AI125231, T32 HL07899, R21 AI116007, R01 AI136500, R21 AI105841]
Co-transplanted allogeneic CD4(+) iNKT cells interact with monocytes and T cells in the graft to coordinate pro-hematopoietic and immunoregulatory pathways in a human umbilical cord blood xenotransplantation model. The nexus of iNKT cells, monocytes, and cord blood T cells leads to enhanced hematopoietic stem and progenitor cell activity and suppression of T-cell inflammatory responses, resulting in successful long-term hematopoietic engraftment without pretransplant conditioning.
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 cotransplanted 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 antibodyproducing human B cells. These results highlight the potential for using iNKT cellular immunotherapy to improve rates of hematopoietic engraftment independently of pretransplant conditioning.
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