NK cell autoreactivity and autoimmune diseases

Abstract

Increasing evidences have pointed out the relevance of natural killer (NK) cells in organ-specific and systemic autoimmune diseases. NK cells bear a plethora of activating and inhibiting receptors that can play a role in regulating reactivity with autologous cells. The activating receptors recognize natural ligands up-regulated on virus-infected or stressed or neoplastic cells. Of note, several autoimmune diseases are thought to be linked to viral infections as one of the first event in inducing autoimmunity. Also, it is conceivable that autoimmunity can be triggered when a dysregulation of innate immunity occurs, activating T and B lymphocytes to react with self-components. This would imply that NK cells can play a regulatory role during adaptive immunity; indeed, innate lymphoid cells (ILCs), comprising the classical CD56(+) NK cells, have a role in maintaining or alternating tissue homeostasis secreting protective and/or pro-inflammatory cytokines. In addition, NK cells display activating receptors involved in natural cytotoxicity and the activating isoforms of receptors for HLA class I that can interact with healthy host cells and induce damage without any evidence of viral infection or neoplastic-induced alteration. In this context, the interrelationship among ILC, extracellular-matrix components, and mesenchymal stromal cells can be considered a key point for the control of homeostasis. Herein, we summarize evidences for a role of NK cells in autoimmune diseases and will give a point of view of the interplay between NK cells and self-cells in triggering autoimmunity.

Keywords: DNAM1; LAIR1; NK cells; NKG2D; autoimmunity; autoreactivity; mesenchymal stromal cells; regulatory NK cells.

Figure 1

Opposite roles of NK cells in autoimmunity. Within microenvironment the interaction of specific NK cell receptor with extracellular-matrix can deliver different signals depending on the type of receptor involved: LAIR1–collagen interaction would lead to inhibition while VLA4-fibronectin engagement to activation. Depending on the type of NK cell subset involved, NK cells show the ability of protecting from the occurrence of autoimmunity (A) through the secretion of immune-regulating cytokines as IL10, TGFβ, IL5, and IL13. In addition, they can eliminate APC and autoreactive T cells through the triggering of activating receptors or regulate tissue homeostasis. On the other hand, NK cells can aggress tissues inducing inflammation through IFNγ production (B), favoring the maturation of APC with the consequent triggering of adaptive immune response. Killing and damaging parenchymal, epithelial, and mesenchymal cells eventually lead to an altered tissue homeostasis and then to autoimmunity. ILC1-3, NKT, and γδT cells are involved and may regulate the NK cell–microenvironment interactions.

Figure 2

Schematic representation of the imbalance between inhibiting and activating receptors on NK cells with the occurrence of autoimmunity and autoimmune disease. (A) In healthy conditions the negative signal (in red) delivered through inhibiting receptors for HLA-I can prevail on the positive signal (in green) induced by the engagement of activating receptor. The net effect is that no damage to self-cells is induced, thus there is no autoreactivity. (B,C) The down-regulation of expression of inhibiting receptors (B) or an increment of activating receptors (C) determines in any case the prevalence of the activating signal on the inhibiting one, leading to self-reactivity (indicated as prevalence of positive signal shown in green). Although not shown, these two situations may also be found together. (D) In this case the lack of activating receptors can lead to impaired blocking of autoreactive T cell clones favoring autoreactivity. For each situation are listed the autoimmune diseases where an alteration of NK receptors have been reported. KIR2DS1 and KIR2DS2 are the activating isoforms of the NK receptor for HLA-C alleles. The KIR2DL1 and KIR2DL2 are the inhibiting isoforms of NK receptors for HLA-C alleles. NKG2C is the activating isoform of CLIR. DNAM1 is an activating receptor present on NK cells and MICA and ULBP are the ligands of the NKG2D surface receptor involved in the recognition of either infected or tumor transformed cells. AA, Alopecia areata; AS, ankylosing spondylitis; ATD, autoimmune thyroid disease; MS, multiple sclerosis; P, psoriasis; PV, pemphigus vulgaris; RA, rheumatoid arthritis; SS, systemic sclerosis; TID, type I diabetes; V, vasculitis.

Figure 3

Hypothesis for the generation of adaptive autoreactivity and autoimmunity. (A) Pathogen associated molecular patterns and/or damage associated molecular patterns (PAMPs and DAMPs) can activate innate immunity interacting with receptors expressed on innate lymphoid cells (NK, ILC subsets, NKT, and γδT lymphocytes). The activation of innate immunity can be regulated by reciprocal interactions among mesenchymal stromal cells (MSC), extracellular-matrix components (EMCs), lymphoid cells, monocyte-derived macrophages (MΦ), and dendritic cells (MoDCs). (B) Innate response elicited by NK, ILC subsets, NKT, and γδT lymphocytes interacting with MSC and EMCs can lead to: (a) rapid elimination of the danger signal that avoids the triggering of adaptive immune cell response; (b) intermediate innate response that leads to the triggering of adaptive immunity with the generation of memory T and B cells; (c) low innate response that determines the persistence of the danger signal leading to generation of autoreactive T and B cells. Autoreactive T and B lymphocytes are controlled by regulatory cells (Treg) but chronic stimulation tends to break the tolerance leading to autoimmune disease.