Graham, Lara V;
Foxall, Russell B;
Ashton-Key, Margaret;
Khakoo, Salim I;
Sayegh, Souraya;
Leandro, Maria;
Reddy, Venkat R;
... Blunt, Matthew D; + view all
(2026)
CD40L and IL-4 Lymph Node-Associated Signals Protect B Cells from Rituximab-Induced ADCC via KIR and NKG2A.
Clinical and Experimental Immunology
, Article uxag001. 10.1093/cei/uxag001.
(In press).
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Abstract
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
| Type: | Article |
|---|---|
| Title: | CD40L and IL-4 Lymph Node-Associated Signals Protect B Cells from Rituximab-Induced ADCC via KIR and NKG2A |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/cei/uxag001 |
| Publisher version: | https://doi.org/10.1093/cei/uxag001 |
| Language: | English |
| Additional information: | © The Author(s) 2026. Published by Oxford University Press on behalf of British Society of Immunology. This is an Open Access art.icle distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) |
| Keywords: | Antibodies, Autoimmunity, Natural Killer Cells |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10220414 |
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