Identifying immunosuppressive human iNKT cells for suppression of GVHD

Our 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. While murine iNKT cells have been shown to suppress GVHD in pre-clinical models, this population of cells is heterogeneous and only certain subsets maintain this suppressive function. In humans, the heterogeneity of iNKT cells is poorly understood, and the subset of human iNKT cells that can best suppress GVHD is currently unknown. We are investigated this using single cell RNA-sequencing, flow cytometry, and functional assays, including suppression of the mixed lymphocyte reaction, cytotoxicity assays, and xenograft GVHD models. Through transcriptomic, proteomic, and functional analyses, we seek to understand human iNKT cell heterogeneity and subset biology and will leverage this preclinical work to develop novel cellular therapies for GVHD prevention and cure.

Transcription factor regulation of iNKT cell-mediated GVHD suppression

Chimeric antigen receptor T (CAR-T) cell therapy can cure certain cancers, but this extremely expensive therapy requires weeks to manufacture from a patient’s own cells. Therefore, patients with rapidly progressing cancer or an inability to access this costly treatment may be unable to benefit. Furthermore, patient T cells may have poor function due to previous chemotherapy, limiting CAR-T cell effectiveness. However, CAR-T cells made from a healthy donor can cause GVHD. Invariant natural killer T cells can be used as a platform for CAR-based cellular therapies to overcome these limitations. Their unique mechanism of activation allows for the use of universal healthy donor cells for a more cost-effective off-the-shelf therapy. Our lab has projects underway to develop and improve CAR-iNKT-based therapies.

Optimizing CAR-iNKT cell therapy

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.

Determining the impact of glycolipid antigen on human iNKT cell function

INKT cells are activated by glycolipid antigens presented by the monomorphic major histocompatibility complex-like protein CD1d. However, little is known about how different glycolipids can skew the function of iNKT cells. Our lab is testing the impact of various glycolipids on iNKT cell function, including in vitro assays and in vivo experimentation.