Fine tuning a well-oiled machine: Influence of NK1.1 and NKG2D on NKT cell development and function

Abstract

Natural killer T cells (NKT) represent a group of CD1d-restricted T-lineage cells that provide a functional interface between innate and adaptive immune responses in infectious disease, cancer, allergy and autoimmunity. There have been remarkable advances in understanding the molecular events that underpin NKT development in the thymus and in the complex array of functions in the periphery. Most functional studies have focused on activation of T cell antigen receptors expressed by NKT cells and their responses to CD1d presentation of glycolipid and related antigens. Receiving less attention has been several molecules that are hallmarks of Natural Killer (NK) cells, but nonetheless expressed by NKT cells. These include several activating and inhibitory receptors that may fine-tune NKT development and survival, as well as activation via antigen receptors. Herein, we review the possible roles of the NK1.1 and NKG2D receptors in regulating development and function of NKT cells in health and disease. We suggest that pharmacological alteration of NKT activity should consider the potential complexities commensurate with NK1.1 and NKG2D expression.

Keywords: Adaptive immunity; NK1.1; NKG2D; NKT cells; Pathogenesis.

Figure 1. Possible effects of NKG2D engagement on peripheral NKT cells

(a) In this model, tonic signaling provided by tissue-expressed NKG2D ligands could help maintain NKT cells in the periphery (b) NKG2D signaling provided by tissue-expressed NKG2D ligands could potentiate the TCR-driven effector functions of NKT cells.

Figure 2. Potentiation of CD8⁺ T cell expansion by NKG2D-null NKT cells

Mixed bone marrow chimeric mice were generated by engrafting irradiated CD45.1 congenic recipients with donor bone marrow mixtures (a) Jα18^−/− plus C57Bl/6 or (b) Jα18^−/− plus NKG2D^−/−. Mice were immunized with OVA plus α-GC before adoptive transfer of CFSE-labeled MHC I-restricted (OVA SIINFEKL-specific) OT-1 cells. After 96 hours splenocytes were harvested and analyzed by flow cytometry. Dot plots on top row show re-constituted NKT cells in the mixed chimeras. Dot plots on center row show OT-1 cells detected by SIINFEKL-loaded MHC 1 pentamers. Histograms on lower row represent dilution of CFSE in the OT-1 cells. Immunization with OVA alone or a heterologous Ag did not lead to OT-1 expansion (not depicted). Jα18^−/− refers to mice with a TCR Jα18 gene segment deletion that lack Type I NKT cells [55]. Data are representative of three mice per group.