CD40LとIL-4がリンパ節で発現し、KIRおよびNKG2Aを介してリツキシマブ誘発ADCCからB細胞を保護する

Autoreactive B cells that remain in lymphatic tissue after anti-CD20 antibody therapy are considered a major contributing factor to relapse in patients with autoimmune diseases. Natural killer (NK) cells contribute to the depletion of autoreactive B cells by rituximab in patients with autoimmune diseases. However, the impact of germinal centre-associated signals CD40L and IL-4 on ADCC was unknown.

This study used a combination of flow cytometry, immunohistochemistry and ex vivo functional assays using PBMCs to investigate how CD40L and IL-4 affect NK cell-B cell interactions.

CD40L and IL-4 significantly upregulate HLA-E and total HLA class I expression on the surface of B cells from healthy donors, as well as patients with rheumatoid arthritis and systemic lupus erythematosus. The upregulation of HLA-E and total HLA functions to inhibit B cell depletion by NK cell-mediated antibody dependent cellular cytotoxicity (ADCC) induced by rituximab via NKG2A and KIR. Moreover, B cells that have differentiated through the germinal centre have higher expression of HLA-E and total HLA compared to naïve B cells and are more resistant to depletion by rituximab. In accordance with this, blockade of NKG2A and inhibitory KIRs by monalizumab and lirilumab, respectively, increased ADCC against autologous B cells in vitro.

Overall, this study identifies a novel mechanism of resistance of B cells to NK cell cytotoxicity and indicates that blockade of the HLA-E:NKG2A and HLA:KIR checkpoint axes could be beneficial for improving B cell depletion in patients with autoimmune diseases.