Exploiting the immunomodulatory potentials of iNKT cells in sepsis and cancer.

Joshua Choi, The University of Western Ontario

Abstract

Invariant natural killer T (iNKT) cells are a unique unconventional T cell subset that recognize glycolipids presented by CD1d expressing cells. The prototypical glycolipid agonist of iNKT cells, α-Galactosylceramide (α-GalCer), can induce the rapid release of an arsenal of cytotoxic effector molecules and enormous amounts of immunomodulatory cytokines as early as two hours after activation. In addition to α-GalCer, various glycolipid agonists are available that allow for specific, in vivo targeting of iNKT cells, and can exert divergent T-helper (T_H)1 and/or T_H2 immune responses. Therefore, the type of response instigated by iNKT cells can profoundly influence the nature of downstream immune response pathways. Sepsis and cancer are two distinct, detrimental pathologies where dysregulated immune responses play a key role in the pathogenesis and disease progression. The extent to which iNKT cells contribute to the pathology of sepsis and cancer has not been fully explored. Furthermore, whether iNKT cells can be targeted by glycolipid immunotherapy to mitigate disease progression has yet to be fully elucidated. In this thesis, the immunomodulatory capacity of iNKT cells were manipulated to skew the host immune response towards a protective phenotype. Firstly, using the surgical cecal ligation and puncture model on C57BL/6 (B6) mice to induce polymicrobial sepsis, iNKT cells were activated with a two-pronged glycolipid immunotherapy. I found that glycolipid treatment conferred significant improvements in sepsis morbidity and mortality. Moreover, glycolipid treatments induced an alteration in the cytokine milieu, restored immunocompetence and NK cell cytotoxicity in septic survivors when compared to vehicle treated controls. Secondly, I discovered a tumoricidal population known as, precursors to mature NK (pre-mNK) cells, that robustly expanded in the liver of naïve B6 mice, upon α-GalCer injection. Notably, in situ expansion of resident hepatic pre-mNK cells was found to be dependent on IL-12 and IL-18 signaling. Moreover, α-GalCer-expanded pre-mNK cells were found to mediate cytotoxicity via the granzyme/perforin pathway and significantly contributed to the anti-metastatic activity of NK cells in vivo. Collectively, the findings reported in this thesis show novel mechanisms by which glycolipid therapies can exploit the immunomodulatory potentials of iNKT cells to ameliorate immunopathologies in sepsis and cancer.