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ABSTRACT Natural killer (NK) cells can recognize virus-infected and stressed cells1 using activating and inhibitory receptors, many of which interact with HLA class I. Although early studies

also suggested a functional impact of HLA class II on NK cell activity2,3, the NK cell receptors that specifically recognize HLA class II molecules have never been identified. We

investigated whether two major families of NK cell receptors, killer-cell immunoglobulin-like receptors (KIRs) and natural cytotoxicity receptors (NCRs), contained receptors that bound to

HLA class II, and identified a direct interaction between the NK cell receptor NKp44 and a subset of HLA-DP molecules, including HLA-DP401, one of the most frequent class II allotypes in

white populations4. Using NKp44ζ+ reporter cells and primary human NKp44+ NK cells, we demonstrated that interactions between NKp44 and HLA-DP401 trigger functional NK cell responses. This

interaction between a subset of HLA-DP molecules and NKp44 implicates HLA class II as a component of the innate immune response, much like HLA class I. It also provides a potential mechanism

for the described associations between HLA-DP subtypes and several disease outcomes, including hepatitis B virus infection5,6,7, graft-versus-host disease8 and inflammatory bowel

disease9,10. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Access

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BEING VIEWED BY OTHERS TLR9 AGONISM DIFFERENTIALLY IMPACTS HUMAN NK CELL-MEDIATED DIRECT KILLING AND ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY Article Open access 25 June 2024 MOUSE AND

HUMAN ANTIBODIES BIND HLA-E-LEADER PEPTIDE COMPLEXES AND ENHANCE NK CELL CYTOTOXICITY Article Open access 28 March 2022 DISTINCT CD16A FEATURES ON HUMAN NK CELLS OBSERVED BY FLOW CYTOMETRY

CORRELATE WITH INCREASED ADCC Article Open access 04 April 2024 DATA AVAILABILITY All figures have associated raw data. All primary data files are available upon request from the

corresponding author. CODE AVAILABILITY All codes are available upon request from the corresponding author REFERENCES * Jost, S. & Altfeld, M. Control of human viral infections by

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23–34 (2007). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This work has been funded in part by the Pathogenesis and the Viral Latency Programs of the Heinrich Pette

Institute, Leibniz Institute for Experimental Virology and the German Center for Infection Research (DZIF) through TTU 04.810. This project has been funded in part with federal funds from

the Frederick National Laboratory for Cancer Research, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the

Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by

the Intramural Research Program of the National Institutes of Health, Frederick National Laboratory, Center for Cancer Research. W.F.G.-B. was supported by National Institute of General

Medical Sciences (T32GM007752) and the NIH (P01-AI104715 and F31AI116366). P.J.N. was supported by NIH U19 NS095774. A.H. was supported by the German Center for Infection Research (DZIF)

through an MD/PhD Stipend (TI 07.002) and via the Clinician Scientist Program of the Faculty of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. J.R was supported by

an Australian Research Council Laureate Fellowship (FL160100049) and R.B was supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia

(APP1109901). We would like to thank H. Reid and K. Loh for their kind gift of HLA-DQ2 viral stocks. We would like to thank the NIH Tetramer Core Facility for all provided HLA class II

monomers. AUTHOR INFORMATION Author notes * Anaïs Chapel Present address: Unité HIV Inflammation et Persistance, Institut Pasteur, Paris, France AUTHORS AND AFFILIATIONS * Research

Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany Annika Niehrs, Wilfredo F. Garcia-Beltran, Angelique Hölzemer, Anaïs

Chapel, Laura Richert, Christian Körner, Glòria Martrus & Marcus Altfeld * German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany Annika

Niehrs, Angelique Hölzemer & Marcus Altfeld * Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA Wilfredo F. Garcia-Beltran & Mary Carrington * Division of Biomedical

Informatics and Personalized Medicine, University of Colorado School of Medicine, Aurora, CO, USA Paul J. Norman * Department of Microbiology and Immunology, University of Colorado School of

Medicine, Aurora, CO, USA Paul J. Norman * Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University,

Clayton, Victoria, Australia Gabrielle M. Watson, Jamie Rossjohn & Richard Berry * Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University,

Clayton, Victoria, Australia Gabrielle M. Watson, Jamie Rossjohn & Richard Berry * First Department of Internal Medicine, University Medical Center Eppendorf, Hamburg, Germany Angelique

Hölzemer * Inserm Inria SISTM Bordeaux Population Health Research Center UMR 1219, Univ. Bordeaux, Bordeaux, France Laura Richert * Department of Microbiology and Biotechnology, University

of Hamburg, Hamburg, Germany Andreas Pommerening-Röser * One Lambda, Inc., Canoga Park, CA, USA Mikki Ozawa & Jar-How Lee * Institute of Infection and Immunity, Cardiff University School

of Medicine, Cardiff, UK Jamie Rossjohn * Basic Science Program, HLA Immunogenetics Section, Frederick National Laboratory for Cancer Research, Frederick, MD, USA Mary Carrington Authors *

Annika Niehrs View author publications You can also search for this author inPubMed Google Scholar * Wilfredo F. Garcia-Beltran View author publications You can also search for this author

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You can also search for this author inPubMed Google Scholar * Marcus Altfeld View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS A.N.

performed reporter cell and primary NK cell experiments and analyzed the data. A.C. and A.N. conducted and analyzed the HLA class II-coated bead assay. A.N., W.F.G.-B. and A.H. designed and

generated the Jurkat reporter cell lines. G.M.W., R.B. and J.R. conducted the SPR measurements. P.J.N., M.O. and J.-H.L. provided the single HLA-DP antigens and gave important intellectual

input. L.R. performed mixed effects linear regression models and provided important statistical guidance. A.N., W.F.G.-B. and M.A. designed the experiments. G.M., C.K., A.P.-R. and M.C. gave

important intellectual input throughout the process. M.A. supervised the study. A.N. wrote the first draft of the manuscript and M.A. revised and edited the manuscript. All authors revised

the manuscript and approved it for publication. CORRESPONDING AUTHOR Correspondence to Marcus Altfeld. ETHICS DECLARATIONS COMPETING INTERESTS A.N., W.F.G.-B. and M.A. filed a patent

application (EP18174760.1) regarding the therapeutic use of anti-NKp44 antibodies for the treatment and/or prevention of graft-versus-host disease. M.O. and J.-H.L. are current employees of

OneLambda Inc., a part of Thermo Fisher Scientific. All other authors declare no competing interest. ADDITIONAL INFORMATION PEER REVIEW INFORMATION: Zoltan Fehervari was the primary editor

on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to

jurisdictional claims in published maps and institutional affiliations. INTEGRATED SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1 KIR3DL1 AND KIR2DL4 FC CONSTRUCTS EXHIBIT UNSPECIFIC

BINDING TO HLA CLASS II COATED BEADS AT HIGH CONCENTRATIONS. A Binding of KIR3DL1 Fc construct at various concentrations (1–100 µg/mL) to HLA-DR (blue), HLA-DQ (yellow) and HLA-DP (red)

coated beads as well as positive (grey) and negative (black) control beads is plotted as median fluorescence intensity (MFI). Each dot represents the measured MFI for binding of the KIR3DL1

Fc construct at a specific concentration to a certain HLA class II coated bead or negative/positive control beads. Lines connect matching MFI values for one specific HLA class II allotype or

negative/positive control beads measured at different KIR3DL1 Fc construct concentrations. Data is representative for one single experiment (n = 1). B MFI values of KIR2DL4 Fc construct

binding at varying concentrations (1–100 µg/mL; left panel) and at 10 µg/mL to HLA-DR (blue), HLA-DQ (yellow) and HLA-DP (red) coated beads as well as positive (grey) and negative (black)

control beads (right panel) are depicted. Each dot in both panels represents one HLA class II molecule. Lines in the left panel connect matching MFI values for one specific HLA class II

allotype or negative/positive control beads measured at different KIR2DL4 Fc construct concentrations. Horizontal line in right panel indicates median, error bars indicate interquartile

range. Data is representative for one single experiment (n = 1). SUPPLEMENTARY FIGURE 2 UNTRANSDUCED JURKAT CELLS DO NOT SHOW FUNCTIONAL RESPONSES TO HLA CLASS II MOLECULES. Activation of

untransduced Jurkat cells in response to anti-KIR2DL3, anti-NKp46, anti-NKp44 as well as HLA-DR7 and HLA-DP401 CLIP monomers was assessed by the expression of CD69. Plot represents one of

eight independent experiments (left panel). The percentage of CD69+ cells following incubation on non-coated wells (blank) was subtracted from all samples. Corrected values are illustrated

as median with interquartile range as determined in eight independent biological replicates (n = 8). SUPPLEMENTARY FIGURE 3 UNSTIMULATED NK CELLS DO NOT EXPRESS NKP44 AND DO NOT DEGRANULATE

UPON CO-INCUBATION WITH HLA-DP401. A Surface expression of NKp44 was determined in freshly isolated untreated (black) and IL-2 plus IL-15 treated (red) primary NK cells. Plot represents one

of seven individual donors. MFI of NKp44 expression from untreated and cytokine-treated primary NK cells was determined in seven individual donors (n = 7). Each dot represents one donor.

Horizontal line indicates the median, error bars display interquartile range. Two-tailed Wilcoxon matched-pairs signed rank test was used to assess differences in the surface expression of

NKp44 between untreated and cytokine-treated primary NK cells. _*p_ = _0.02_. B Freshly isolated unstimulated NK cells were isolated from seven individual donors and co-incubated with

plate-coated anti-NKp44, HLA-DR7 CLIP, HLA-DP401 CLIP or non-coated wells (blank) in the presence of purified mouse IgG1 isotype or purified anti-human NKp44 antibody (both at a final

concentration of 10 µg/mL). The percentage of CD107a+ cells was determined. Each dot represents one individual donors (n = 7) and lines connect responses from one individual donor.

SUPPLEMENTARY FIGURE 4 HLA-DP SURFACE EXPRESSION OF JE6.1-DP TRANSDUCED CELL LINES IS INCREASED BY CLIP PULSING. A HLA-DP surface expression of HLA-DP transduced cell lines (red and blue

histograms) is depicted. The HLA-DP expression of the untransduced parental cell line is displayed in grey. Plots represent one of seven individual experiments. B HLA-DP (left panel) and

CLIP (right panel) surface expression following CLIP pulsing in comparison to DMSO-treated cells is depicted as fold change in MFI [MFI CLIP pulsed/MFI DMSO] for the four indicated JE6.1-DP

expressing cell lines. Each dot represents one individual biological replicate as determined in seven independent experiments (n = 7). Boxes represent 25th to 75th percentiles. Whiskers

indicate minimum and maximum values, horizontal line indicates the median. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary Figs. 1–4 and Supplementary Tables 1 and 2

REPORTING SUMMARY RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Niehrs, A., Garcia-Beltran, W.F., Norman, P.J. _et al._ A subset of HLA-DP molecules

serve as ligands for the natural cytotoxicity receptor NKp44. _Nat Immunol_ 20, 1129–1137 (2019). https://doi.org/10.1038/s41590-019-0448-4 Download citation * Received: 13 September 2018 *

Accepted: 06 June 2019 * Published: 29 July 2019 * Issue Date: September 2019 * DOI: https://doi.org/10.1038/s41590-019-0448-4 SHARE THIS ARTICLE Anyone you share the following link with

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