Innate Lymphoid Cells - Neglected Players in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a highly debilitating autoimmune disease affecting millions of individuals worldwide. Although classically viewed as T-cell mediated disease, the role of innate lymphoid cells (ILC) such as natural killer (NK) cells and ILC 1-3s has become a focal point as several findings implicate them in the disease pathology. The role of ILCs in MS is still not completely understood as controversial findings have been reported assigning them either a protective or disease-accelerating role. Recent findings in experimental autoimmune encephalomyelitis (EAE) suggest that ILCs infiltrate the central nervous system (CNS), mediate inflammation, and have a disease exacerbating role by influencing the recruitment of autoreactive T-cells. Elucidating the detailed role of ILCs and altered signaling pathways in MS is essential for a more complete picture of the disease pathology and novel therapeutic targets. We here review the current knowledge about ILCs in the development and progression of MS and preclinical models of MS and discuss their potential for therapeutic applications.

Keywords: autoimmune disease; disease-modifying therapies (DMTs); experimental autoimmune encephalomyelitis (EAE); innate lymphoid cells (ILCs); multiple sclerosis; natural killer cells.

Figure 1

ILCs, their transcription factors, and cytokines. Figure 1 depicts the ILC family, their transcription factors, and cytokines in mice. NK cells are transcription factor T-bet and Eomes dependent cytotoxic ILCs that release cytokines IFN-γ, and TNF together with cytotoxic molecules such as perforin, and granzyme. ILC1-3 and LTis are non-cytotoxic ILCs. ILC1s are dependent on the transcription factors Tbet, NFIL3, and RUNX2 and release IFN-γ, TNF, and IL-4. ILC2s are dependent on the transcription factors RORα, GATA3, Bcl11B, and GFI and release IL-4, IL-5, IL-9, IL-14, and transcription factor Areg. ILC3s are dependent on the transcription factors RORγt, AHR, and ID2 and release TNF, IFN-γ, IL-22, GM-CSF, and IL-17A. LTis are dependent on the transcription factors RORγt, TOX, and ID2 and release IL-17A, GM-CSF, and IL-22. Abbreviations of transcription factors: NFIL3, nuclear factor IL-3 induced; ID2, inhibitor of DNA binding 2; TOX, thymocyte selection associated high mobility group box protein; GATA3, GATA binding protein 3; T-BET, T-box transcription factor; EOMES, Eomesodermin; RUNX3, runt-related transcription factor 3; RORα, RAR-related orphan recepto;, Bcl11b, B cell lymphoma/leukemia 11B; RORγt, RAR- related orphan receptor γt; and AhR, Aryl hydrocarbon receptor. Abbreviations of cytokines: IFN-γ, Interferon-gamma; TNF, Tumor necrosis factor-alpha; IL, Interleukin; GM-CSF, Granulocyte-macrophage colony-stimulating-factor; Areg, amphiregulin.

Figure 2

Schematic Overview of potential pathophysiology of MS and role of ILCs. T-cells and B-cells infiltrate the CNS through a leaky blood-brain barrier whereby ILC subtypes that reside in the meninges release pro-inflammatory cytokines that influence the extent of CD4⁺ T-cell infiltration into the CNS. T-cells interact with B-cells and release cytokines and antibodies that cause inflammation which damages the myelin sheath of neurons and thereby induce demyelination. NK cells can also kill oligodendrocytes directly thereby potentially contributing to the extent of demyelination of the neurons. ILC2s are assumed to play a role in demyelination. LTis are assumed to play a role in the development of ELFs.