Novel Oral Adjuvant to Enhance Cytotoxic Memory Like NK Cell Responses in HIV Vaccine Platform

Overview

Journal NPJ Vaccines

Date 2025 Jan 11

PMID 39799133

Authors

Mario Alles

Manuja Gunasena

Christina Isckarus

Ilmini De Silva

Sarah Board

Will Mulhern

Patrick L Collins

Thorsten Demberg

Namal P M Liyanage

Affiliations

Soon will be listed here.

Abstract

Natural killer (NK) cell-driven effector mechanisms, such as antibody-dependent cell-mediated cytotoxicity, emerged as a secondary correlate of protection in the RV144 HIV vaccine clinical trial, the only vaccine thus far demonstrating some efficacy in human trials. Therefore, leveraging NK cells with enhanced cytotoxic effector responses may bolster vaccine-induced protection against HIV. Here, we investigated the effect of orally administering indole-3-carbinol (I3C), an aryl hydrocarbon receptor (AHR) agonist, as an adjuvant to an RV144-like vaccine platform in a mouse model. We demonstrate the expansion of KLRG1-expressing NK cells induced by the vaccine together with I3C. This NK cell subset exhibited enhanced vaccine antigen-specific cytotoxic memory-like features. Our study underscores the potential of incorporating I3C as an oral adjuvant to HIV vaccine platforms to enhance antigen-specific cytotoxicity of NK cells against HIV-infected cells. This approach may contribute to enhancing the protective efficacy of HIV preventive vaccines against HIV acquisition.

References

Bhatnagar N, Ahmad F, Hong H, Eberhard J, Lu I, Ballmaier M . FcγRIII (CD16)-mediated ADCC by NK cells is regulated by monocytes and FcγRII (CD32). Eur J Immunol. 2014; 44(11):3368-79. DOI: 10.1002/eji.201444515. View

Abel A, Yang C, Thakar M, Malarkannan S . Natural Killer Cells: Development, Maturation, and Clinical Utilization. Front Immunol. 2018; 9:1869. PMC: 6099181. DOI: 10.3389/fimmu.2018.01869. View

Omi A, Enomoto Y, Kiniwa T, Miyata N, Miyajima A . Mature resting Ly6C(high) natural killer cells can be reactivated by IL-15. Eur J Immunol. 2014; 44(9):2638-47. DOI: 10.1002/eji.201444570. View

Rahim M, Tu M, Mahmoud A, Wight A, Abou-Samra E, Lima P . Ly49 receptors: innate and adaptive immune paradigms. Front Immunol. 2014; 5:145. PMC: 3980100. DOI: 10.3389/fimmu.2014.00145. View

Neavin D, Lee J, Liu D, Ye Z, Li H, Wang L . Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand-Dependent Gene Expression. Drug Metab Dispos. 2019; 47(9):983-994. PMC: 7184190. DOI: 10.1124/dmd.119.087312. View

Fogel L, Sun M, Geurs T, Carayannopoulos L, French A . Markers of nonselective and specific NK cell activation. J Immunol. 2013; 190(12):6269-76. PMC: 3679313. DOI: 10.4049/jimmunol.1202533. View

Dorries R . The role of T-cell-mediated mechanisms in virus infections of the nervous system. Curr Top Microbiol Immunol. 2001; 253:219-45. DOI: 10.1007/978-3-662-10356-2_11. View

Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R . Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009; 361(23):2209-20. DOI: 10.1056/NEJMoa0908492. View

Sun L . Recent advances in the development of AHR antagonists in immuno-oncology. RSC Med Chem. 2021; 12(6):902-914. PMC: 8221258. DOI: 10.1039/d1md00015b. View

10.

Jost S, Lucar O, Lee E, Yoder T, Kroll K, Sugawara S . Antigen-specific memory NK cell responses against HIV and influenza use the NKG2/HLA-E axis. Sci Immunol. 2023; 8(90):eadi3974. PMC: 11104516. DOI: 10.1126/sciimmunol.adi3974. View

11.

Rydyznski C, Cranert S, Zhou J, Xu H, Kleinstein S, Singh H . Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers. Cell Rep. 2018; 24(13):3367-3373.e4. PMC: 6192537. DOI: 10.1016/j.celrep.2018.08.075. View

12.

de Saint Basile G, Menasche G, Fischer A . Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol. 2010; 10(8):568-79. DOI: 10.1038/nri2803. View

13.

Wijaya R, Read S, Schibeci S, Eslam M, Azardaryany M, El-Khobar K . KLRG1+ natural killer cells exert a novel antifibrotic function in chronic hepatitis B. J Hepatol. 2019; 71(2):252-264. DOI: 10.1016/j.jhep.2019.03.012. View

14.

Good-Jacobson K, Szumilas C, Chen L, Sharpe A, Tomayko M, Shlomchik M . PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol. 2010; 11(6):535-42. PMC: 2874069. DOI: 10.1038/ni.1877. View

15.

Fu B, Wang F, Sun R, Ling B, Tian Z, Wei H . CD11b and CD27 reflect distinct population and functional specialization in human natural killer cells. Immunology. 2011; 133(3):350-9. PMC: 3112344. DOI: 10.1111/j.1365-2567.2011.03446.x. View

16.

Coelho A, Schaller M, Benjamim C, Orlofsky A, Hogaboam C, Kunkel S . The chemokine CCL6 promotes innate immunity via immune cell activation and recruitment. J Immunol. 2007; 179(8):5474-82. DOI: 10.4049/jimmunol.179.8.5474. View

17.

Pullyblank A, Guillou P, Monson J . Interleukin 1 and tumour necrosis factor alpha may be responsible for the lytic mechanism during anti-tumour antibody-dependent cell-mediated cytotoxicity. Br J Cancer. 1995; 72(3):601-6. PMC: 2033875. DOI: 10.1038/bjc.1995.380. View

18.

Das J . Activation or tolerance of natural killer cells is modulated by ligand quality in a nonmonotonic manner. Biophys J. 2010; 99(7):2028-37. PMC: 3042567. DOI: 10.1016/j.bpj.2010.07.061. View

19.

Shin J, Zhang L, Murillo-Sauca O, Kim J, Kohrt H, Bui J . Modulation of natural killer cell antitumor activity by the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A. 2013; 110(30):12391-6. PMC: 3725066. DOI: 10.1073/pnas.1302856110. View

20.

Singh R, Bassett E, Chakravarti A, Parthun M . Replication-dependent histone isoforms: a new source of complexity in chromatin structure and function. Nucleic Acids Res. 2018; 46(17):8665-8678. PMC: 6158624. DOI: 10.1093/nar/gky768. View