Identifying immunosuppressive human iNKT cells for suppression of GVHD

A current focus of the lab is investigating the role of invariant natural killer T (iNKT) cells in graft-versus-host disease (GVHD), which have particular promise as a therapeutic. Murine iNKT cells have been shown to suppress GVHD in pre-clinical models, yet we have shown in studies of murine iNKT cell heterogeneity that only certain subsets maintain this function. However, the heterogeneity of human iNKT cells is poorly understood, and which subset of human iNKT cells can best suppress GVHD is unknown. This is now being investigated in our lab with single cell RNA-sequencing, flow cytometry, and functional assays, including suppression of the mixed lymphocyte reaction, cytotoxicity assays, and in xenograft GVHD models. Through transcriptomic, proteomic, and functional analyses, we seek to understand human iNKT cell heterogeneity and subset biology and leverage this preclinical work to develop novel cellular therapies for GVHD prevention and cure.

Engineering human iNKT cells to enhance GVHD suppression

Pre-clincial models of hematopoietic stem cell transplantation have shown that the adoptive transfer of murine invariant natural killer T (iNKT) cells significantly reduces graft-versus-host disease (GVHD). However, acquiring the right population of iNKT cells in sufficient quantities to attempt a similar approach in humans may prove elusive. Therefore, we are investigating novel approaches to engineer human iNKT cells to enhance their ability to suppress GVHD. Through techniques such as lentiviral transduction to overexpress immunomodulatory proteins or CRISPR/Cas9 to target similar pathways, we seek to modulate human iNKT cells to enhance their potential as a cellular therapy for GVHD.

Elucidating plasticity of iNKT cell subsets

While the existence of functionally distinct immunophenotypic subsets of murine invariant natural killer (iNKT) cells has been clearly demonstrated, it remains unclear whether these are fixed phenotypes or whether there is plasticity in the subsets. In this project, we will leverage mice with no endogenous iNKT cells (Jalpha18-/- mice) to study the capacity of iNKT subsets to convert into alternative immunophenotypes. We will further explore the impact of various stressors on this capacity as well as the importance of localization. Our goal is to deepen our understanding of iNKT cell biology and use this to inform subsequent studies of iNKT cells in health and disease.