Low-dose IL-2 induces CD56bright NK regulation of T cells via NKp44 and NKp46

Abstract

Low-dose interleukin (IL)-2 has shown clinical benefits in patients with autoimmune and inflammatory diseases. Both regulatory T cells (T regs ) and natural killer (NK) cells are increased in response to low-dose IL-2 immunotherapy. The role of regulatory T cells in autoimmune diseases has been extensively studied; however, NK cells have not been as thoroughly explored. It has not been well reported whether the increase in NK cells is purely an epiphenomenon or carries actual benefits for patients with autoimmune diseases. We demonstrate that low-dose IL-2 expands the primary human CD56 bright NK cells resulting in a contact-dependent cell cycle arrest of effector T cells (T effs ) via retention of the cycle inhibitor p21. We further show that NK cells respond via IL-2R-β, which has been shown to be significant for immunity by regulating T cell expansion. Moreover, we demonstrate that blocking NK receptors NKp44 and NKp46 but not NKp30 could abrogate the regulation of proliferation associated with low-dose IL-2.The increase in NK cells was also accompanied by an increase in T reg cells, which is dependent on the presence of CD56 bright NK cells. These results not only heighten the importance of NK cells in low-dose IL-2 therapy but also identify key human NK targets, which may provide further insights into the therapeutic mechanisms of low-dose IL-2 in autoimmunity.

Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases?

“…These data, in addition to the observation from animal models with RA (115) and that the TIGIT expression levels on human NK cells was associated with functional heterogeneity among healthy individuals leading to different susceptibilities to infection, autoimmune disease, and cancer, support the importance of TIGIT as a powerful negative regulator of NK cells in SLE, whose activation could represent a potential therapeutic strategy (116). NK cells can represent potential therapeutic targets as also demonstrated by their response to low-dose IL-2 immunotherapy (117). GM-CSF-secreting NK cells have an important role in the inflammatory cellular cascade involved in the amplification of joint inflammation and in the persistence of autoantibody-driven arthritis (118).…”

CD56^brightCD16^– natural killer cells as an important regulatory mechanism in chronic graft-<I>versus</i>-host disease

“…Based on the transcriptome study results and previous studies, 10 we investigated the role of the GPR183, NKp44, and NKp46 receptors in the NK reg suppressive mechanism. We blocked GPR183R using the antagonist NIBR189 and NKp44 and NKp46 using blocking monoclonal antibodies.…”

“… 9 While the association of T reg expansion and therapeutic outcome is considered the primary explanation, an alternative mechanism was identified as cGvHD inhibition being mediated by a CD56bright NK cell contact‐dependent cell cycle arrest of effector T cells through the NK receptors NKp44 and NKp46. 10 Further, low dose IL-2 as treatment of systemic lupus erythematosus has shown to successfully suppress disease activity through both an increase in T reg cells and NK cells. 11 Similarly, recent evidence supports that ECP therapy suppresses cGvHD primarily through increased CD56 bright NK cells.…”

Natural killer cells in the central nervous system

“…The immunoregulative role of NK cells are enhanced after some MS therapies. Interferon β(IFN-β) is a well-known disease-modifying therapy designed for relapsing remitting MS(RRMS), the possible mechanism of which includes the increased number of CD56 bright NK cells after treatment [ 74 , 75 ]. Daclizumab is a therapeutic humanized monoclonal antibody targeting CD25 to abolish high-affinity IL2-R, which was once approved for the treatment of adult MS owing to the promising clinical effects but has been withdrawn nowadays due to its severe adverse events [ 68 , 76 ].…”

“…However, there is a remarkable expansion of CD56 bright NK cells accompanied by a significant reduction in the ratios of CD4 + T/NK and CD8 + T/NK cells in both the CSF and peripheral blood of patients administered with daclizumab [ 63 , 78 ]. That’s likely because CD56 bright NK cells express great abundance of CD122 with intermediate IL-2 affinity and bind excess IL-2 after CD25 blockade [ 74 , 79 ]. Additionally, a differentiation switch of ILCs from lymphoid tissue inducer (LTi) cells to NK cell lineage occurs after applying daclizumab, contributing to enlarging NK cells [ 80 ].…”