The pathogenesis of autoimmunity remains to be fully elucidated, although the contribution of genetic and environmental factors is generally recognized. Despite autoimmune conditions are principally due to T and B lymphocytes, NK cells also appear to play a role in the promotion and/or maintenance of altered adaptive immune responses or in peripheral tolerance mechanisms.

Although NK cells are components of the innate immune system, they shows characteristics of the adaptive immune system, such as the expansion of pathogen-specific cells, the generation of long-lasting “memory” cells able to persist upon cognate antigen encounter, and the possibility to induce an increased secondary recall response to re-challenge.

Human NK cells are generally identified as CD56⁺ CD3⁻, conversely CD56⁺ CD3⁺ cells represent a mixed population of NK-like T (NK T) cells and antigen-experienced T cells showing the up-regulation of several NK cell markers. CD56^dim constitute about 90% of NK cells in the peripheral blood, they are mature and involved in cytotoxicity responses; CD56^bright instead are more immature, mostly involved in cytokine production, having only a limited role in cytolytic responses, keen to leave the blood vessels as the principal population observed in lymph nodes. NK cells have been identified also in non-lymphoid tissues since, in pathologic conditions, they can quickly reach the target organs. A cross-talk between NK with dendritic cells and T cells is established throughout different receptor-ligand bindings.

Several studies support the correlation between NK cell number and/or functional alterations, such as a defective cytotoxic activity and several autoimmune conditions. Among the different autoimmune pathologies and even within the same disease, NK cell function is significantly different either promoting or even protecting against the onset of the autoimmune condition.

In this Review, we discuss recent literature supporting the role played by NK cells, as a bridge between innate and adaptive immunity, in the onset of autoimmune diseases.