Modulation of T helper cell functions by stress-sensing receptor NKG2D
Final Report Abstract
Elucidating the basis of chronicity and suggesting appropriate treatments for inflammatory diseases represents a big challenge for medical science, as the mechanisms driving aberrant immune responses are mostly unknown and deserve further study. Of particular interest is the identification of checkpoints which regulate the function and differentiation of proinflammatory cells during pathogenesis, along with methods for their modulation for therapeutic purposes. Natural Killer Group 2, Member D (NKG2D) is a potent activator of the immune system, known as a sentinel for “induced-self” ligands, i.e., cellular danger signals presented by cells undergoing tumor transformation, endoplasmic reticulum (ER) stress, cell death or viral infection or being exposed to an inflammatory cytokine milieu. Sensing those ligands can be translated by NKG2D into activation of natural killer (NK) cells or co-stimulation of different subsets of T cells, thus contributing to the regulation of the inflammatory response. This project was devoted to understand the signals that drive the expression of NKG2D on CD4+ T cells and to study the role of NKG2D in regulating CD4+ T cells differentiation and effector functions in vitro and in vivo. We addressed the role of NKG2D in Th cells in two Th17/Th17-mediated models of inflammatory diseases, antigen-induced arthritis (OIA) and experimental autoimmune encephalomyelitis (EAE) model, mimicking rheumatoid arthritis and multiple sclerosis, respectively. In both models, NKG2D marked cells with high proinflammatory potential, i.e., cells expressing high levels of IL-17A, IFN-γ and GM-CSF, and while we did not observe any impact of NKG2D-deficiency on the formation of the antigenspecific CD4+ T cell pool, it did impact their effector potential. In line with that, mice with NKG2D-deficiency in T cells exhibited less severe form of arthritis and EAE. By employing extensive cell culturing and RNA sequencing techniques we could show that NKG2D is specifically upregulated in Th1 and T-bet+ Th17 cells, but virtually absent on Th2 and a pool of naïve cells in vitro. Importantly, NKG2D up-regulation on Th1/Th17 cells was accompanied by the expression of a whole repertoire of innate receptors, suggesting that during inflammation even adaptive lymphocytes are armed with innate sensors, enabling these cells to additionally respond to microenvironmental stress cues. Altogether, our findings suggest that NKG2D might represent an important checkpoint target for Th1/Th17-mediated inflammatory diseases.
Publications
- NK cell receptor NKG2D enforces proinflammatory features and pathogenicity of Th1 and Th17 cells. J Exp Med. 2020 Aug 3;217(8):e20190133
Babic M, Dimitropoulos C, Hammer Q, Stehle C, Heinrich F, Sarsenbayeva A, Eisele A, Durek P, Mashreghi MF, Lisnic B, Van Snick J, Löhning M, Fillatreau S, Withers DR, Gagliani N, Huber S, Flavell RA, Polic B, Romagnani C
(See online at https://doi.org/10.1084/jem.20190133)
