Natural killer cells and autoimmunity

Abstract

Autoimmune diseases are often characterized as clinical syndromes caused by the inappropriate activation of T or B cells resulting in systemic or organ-specific damage. However, studies support a role for the innate immune system, and in particular natural killer (NK) cells, in stimulating or suppressing autoimmunity. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in modulating T and B cell-mediated autoimmunity.

Figure 1

Natural killer (NK) cell activation is controlled by the integration of signals from activation and inhibitory receptors. (a) Inhibitory NK cell receptors recognize self MHC class I and restrain NK cell activation. (b) When unimpeded by the inhibitory receptors, binding of NK cell activation receptors to their ligands on target cells results in NK cell stimulation. In the absence or downregulation of self MHC class I on the target cells, these stimulatory signals are no longer suppressed, resulting in NK cell responses including cytokine production and granule release leading to cytotoxicity. Note that this model indicates that NK cells do not kill by default; that is, when MHC class I inhibition is absent, the NK cell must still be stimulated through activation receptors. Moreover, whether or not an individual NK cell is activated by a target is determined by this complex balance of receptors with opposing function and expression of the corresponding ligands. In general, however, inhibition dominates over activation. Finally, NK cells can be directly stimulated by cytokines such as interleukin-12 that trigger the production of other cytokines by NK cells (not shown). These direct cytokine-mediated responses are not affected by MHC class I expression.

Figure 2

Murine models show that natural killer (NK) cells affect autoimmunity through several potential mechanisms. (a) NK cells limit viral-induced tissue damage by directly killing virally infected cells or by releasing cytokines that can suppress viral propagation either directly or indirectly by activating other cells such as macrophages. Defective NK cell responses to viral infections may result in autoimmunity in genetically predisposed strains of mice as a result of uncontrolled infection leading to increased tissue destruction, with accompanying exposure of self antigens. (b) NK cells participate in the immunoregulation of other immune cells. Control of autoreactive T and B cells by NK cells may be mediated directly through the release of cytokines and chemokines or indirectly through bidirectional interactions with other components of the innate immune system such as dendritic cells (DCs). In addition, it is possible that NK cells may kill autoreactive lymphocytes or inappropriately activated immature DCs. (c) NK cells could potentially mediate an autoimmune response by inappropriately killing normal tissues.