PT - JOURNAL ARTICLE AU - Nicholas J Hess AU - Nikhila S Bharadwaj AU - Elizabeth A Bobeck AU - Courtney E McDougal AU - Shidong Ma AU - John-Demian Sauer AU - Amy W Hudson AU - Jenny E Gumperz TI - iNKT cells coordinate immune pathways to enable engraftment in nonconditioned hosts AID - 10.26508/lsa.202000999 DP - 2021 Jul 01 TA - Life Science Alliance PG - e202000999 VI - 4 IP - 7 4099 - https://www.life-science-alliance.org/content/4/7/e202000999.short 4100 - https://www.life-science-alliance.org/content/4/7/e202000999.full SO - Life Sci. Alliance2021 Jul 01; 4 AB - 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.