Multiple sclerosis: characterisation of NK and innate lymphoid cell subsets

Abstract

Natural killer cells (NKC) are innate lymphocytes associated with viral recognition and tumour immunology. NKC are also implicated in autoimmunity and studies have suggested both pathogenic and regulatory roles in multiple sclerosis (MS). The aim of this thesis was to analyse NKC subsets in MS in greater detail. Work in the Boyton/Altmann laboratory identified distinct subsets of NKC that were CD56dimCD27-CD57+CD8+ (DP) and CD56dimCD27-CD57-CD8- (TN), that show altered frequency in patients with MS. It was suggested that a proportion of cells in the TN subset might be better characterised as innate lymphoid cells (ILC) due to their expression of c-Kit and IL-7R. Here, detailed transcriptomic analysis of these two NKC subsets by RNA-sequencing suggests that indeed, the TN subset is either itself, or contains a population that can be, better defined as c-Kit+ ILC2 or ILC3. Genes expressed included KIT and IL-7R as well as NKX3-1, IL1RL1 (the receptor for IL-33) and TNFRS19. Furthermore, this subset expressed genes associated with HLA-II antigen presentation as well as the costimulatory receptors, CD80 and CD86. DP and TN NKC expressed markers associated with trafficking towards and transmigration across the blood-brain barrier. Furthermore, in vitro transmigration assays showed TN NKC migrated towards supernatant from myelin peptideactivated PBMC. Relapsing MS patients had an increased percentage of c-Kit+ILC2 in peripheral blood when compared to stable MS patients and healthy controls. This supports a potential role for c-Kit+ILC2 and perhaps a subset of TN NKC that might be better described as c-Kit+ ILC2, in MS relapse and highlights these cells as a subject for further investigation, given that the literature describe a similar subset in murine EAE, able to attenuate Th17 polarised responses via the production of type- 2 cytokines. The findings suggest the potential for new MS therapeutics based on biologics to modulate NKC subsets.