ProjectiNKT – Tolerogenic Invariant Natural Killer T Cells for Protection from Lethal GVHD

iNKT

Tolerogenic Invariant Natural Killer T Cells for Protection from Lethal GVHD

7/1/2015 to 6/30/2017

Adoptively transferred iNKT cells protect from GVHD in murine models of allogeneic HCT through expansion and activation of donor Tregs but the humoral and cellular mechanisms underlying this phenomenon are poorly understood. We plan to elucidate the role of iNKT cells within the complex immunoregulatory network of Tregs, MDSCs and alloreactive T cells. We hypothesize that iNKT cells promote the expansion of donor Tregs through MDSCs in an IL-4/IL-13 dependent manner. Adoptively transferred iNKT cells secrete IL-4 and IL-13 which may both bind to the IL-4 receptor on MDSCs inducing cellular activation through STAT6 signaling. We plan to use different knock-in and knock-out mouse strains, monoclonal blocking antibodies, conventional flow cytometry, fluorescence-activated cell sorting, CyTOF and bioluminescence imaging together with our well-established murine models of allogeneic HCT. We hope that elucidating the precise mechanism of Treg expansion through iNKT cells might open new avenues to prevent GVHD which still causes significant morbidity and mortality after allogeneic HCT.