Dynamic Regulation of NKG2A/CD94 Checkpoint and MHC-E Ligand Presentation by the Peptide Loading Complex in Cancer Immunotherapy


The immune checkpoint NKG2A/CD94 is part of the immune system’s complex regulation mechanism, specifically involved in modulating the immune response. It is a receptor found on the surface of certain immune cells, including some types of Natural Killer (NK) cells and T cells. The NKG2A/CD94 complex binds to the non-classical Major Histocompatibility Complex (MHC) class I molecule, HLA-E, in humans (or Qa-1 in mice). This interaction plays a key role in the immune system’s ability to distinguish between healthy cells and those that are infected or undergoing stress. When NKG2A/CD94 engages with its ligand (HLA-E), it sends inhibitory signals to the NK cell or T cell it is expressed on. This inhibitory signal reduces the activity of these cells, preventing the destruction of the target cell that presents HLA-E. This mechanism is crucial for preventing autoimmune reactions and controlling the immune response to ensure it is proportionate to the threat. In cancer and chronic viral infections, this inhibitory pathway can be exploited by diseased cells to avoid immune detection and destruction. Consequently, blocking the NKG2A/CD94 pathway has emerged as a potential therapeutic strategy to enhance the immune system’s ability to target and eliminate cancer cells or cells infected with chronic viruses. The inhibition of NKG2A/CD94 interaction with its ligands has been explored as a therapeutic approach in cancer immunotherapy. By blocking this checkpoint, the goal is to release the brakes on NK cells and certain T cells, enhancing their ability to recognize and kill cancer cells. Several antibodies targeting NKG2A have been developed and are being investigated in clinical trials to determine their efficacy in treating various types of cancer.   To this account a new study led by Professor Jon Weidanz from the University of Texas and Professor Thorbald van Hall from the Leiden University Medical Center, published in Cell Reports, sheds new light on the immunological mechanism through which the NKG2A/CD94 checkpoint functions in cancer immunotherapy. This comprehensive research elucidates the pivotal role of the immune checkpoint NKG2A/CD94 and its ligand, major histocompatibility complex E (MHC-E), in modulating lymphocyte activity in the context of cancer. By employing a novel nanobody specific for the Qdm/Qa-1b complex (the mouse equivalent of the human NKG2A/CD94 ligand), the study reveals intricate details about the antigen processing and presentation machinery, offering a deeper understanding of how and when these immune components are presented in situ. The study focuses on the presentation of specific leader peptides within MHC-E, crucial for the NKG2A/CD94-mediated inhibition, and explores their dependency on the peptide-loading complex within the endoplasmic reticulum. One of the key findings of this research is the dependency of Qdm peptide presentation on every member of the endoplasmic reticulum-resident peptide loading complex, highlighting the complex’s comprehensive role in antigen processing. This peptide, pivotal for NKG2A/CD94 engagement, is not widely presented in homeostasis but is induced by inflammatory signals, suggesting a dynamic regulation in response to cellular stress or disease. Furthermore, the study identifies LILRB1 as a functional inhibitory receptor for MHC-E in steady state, broadening our understanding of immune regulation beyond the previously known NKG2A/CD94 checkpoint. This discovery suggests that MHC-E serves as a convergent ligand for multiple immune checkpoints, each playing a unique role in modulating immune responses under various physiological conditions.

The authors also highlighted the rapid turnover rate of the Qdm peptide, underscoring the dynamic nature of antigen presentation and the immune system’s adaptability in responding to rapidly changing cellular environments. This real-time reflection of antigen processing capacity has significant implications for the development of targeted immunotherapies, offering potential for more precise modulation of immune responses against cancer. In conclusion, the study by Weidanz and van Hall provides critical insights into the molecular mechanisms governing the NKG2A/CD94 checkpoint and its ligand MHC-E, expanding our knowledge of immune regulation in cancer. The identification of LILRB1 as an additional receptor for MHC-E and the elucidation of the peptide loading complex’s role in Qdm presentation pave the way for novel therapeutic strategies in cancer immunotherapy, potentially improving outcomes for patients with various malignancies.

Dynamic Regulation of NKG2A/CD94 Checkpoint and MHC-E Ligand Presentation by the Peptide Loading Complex in Cancer Immunotherapy - Medicine Innovates
Image Credit: Cell Reports 2023 42DOI: (10.1016/j.celrep.2023.113516)

About the author

Thorbald van Hall
Professor Tumour immunology
Leiden University Medical Center

Professor of experimental tumorimmunology. Thorbald van Hall is member of the Dutch society of Immunology (NVVI) and the European and American societies of tumor immunologists (EATI and CIMT).

About the author

Professor Jon Weidanz
The University of Texas at Arlington

Jon Weidanz, MPH, Ph.D. is the Associate Vice President for Research, Professor with tenure, College of Nursing and Health Innovation and College of Engineering, and a member of the Multi-Professional Center for Health Informatics at the University of Texas at Arlington (UTA). He founded the North Texas Genome Center at UTA in 2018 and served as its director until 2022. Dr. Weidanz has broad experience and interest in biotechnology with particular knowledge and expertise in immunology and immunotherapy research and product development. He has more than 60 peer-reviewed articles, book chapters and published conference proceedings and has been an invited speaker at more than 50 conferences, universities and companies.


Middelburg J, Ghaffari S, Schoufour TAW, Sluijter M, Schaap G, Göynük B, Sala BM, Al-Tamimi L, Scheeren F, Franken KLMC, Akkermans JJLL, Cabukusta B, Joosten SA, Derksen I, Neefjes J, van der Burg SH, Achour A, Wijdeven RHM, Weidanz J, van Hall T. The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent. Cell Rep. 2023 Dec 26;42(12):113516. doi: 10.1016/j.celrep.2023.113516.

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