Document Type
Article
Publication Date
1-1-2026
Original Citation
Khan N,
Frank K,
Paust S.
CXCR6+ natural killer cell immunotherapy preserves CD4+ T helper cells in humanized mice Front Immunol. 2026;17:1888755.
Keywords
JGM, Animals, Killer Cells, Natural, Humans, Receptors, CXCR6, HIV Infections, Mice, HIV-1, T-Lymphocytes, Helper-Inducer, Immunotherapy, Adoptive, env Gene Products, Human Immunodeficiency Virus
JAX Source
Front Immunol. 2026;17:1888755.
ISSN
1664-3224
PMID
42639078
DOI
https://doi.org/10.3389/fimmu.2026.1888755
Grant
The author(s) declared financial support was received for this work and/or its publication. This study was supported by the National Institutes of Health through grants R01AI161014 and R21AI170555 awarded to SP, and by seed funding from The Jackson Laboratory for Genomic Medicine (to SP)
Abstract
Human immunodeficiency virus (HIV) persists despite antiretroviral therapy because long-lived viral reservoirs are not eliminated, and ongoing or rebound infection contributes to progressive loss of CD4+ T helper cells. Natural killer (NK) cells can acquire adaptive, antigen-experienced functions, including recall responses to HIV envelope protein, suggesting that defined NK-cell subsets may be therapeutically useful against HIV. Because HIV-responsive adaptive NK-cell activity is enriched among CXC chemokine receptor 6-positive (CXCR6+) NK cells, we tested whether CXCR6+ NK cells provide enhanced antiviral activity and CD4+ T-cell protection compared with CXCR6− NK cells. In co-cultures with HIV-infected primary CD4+ T cells, PBMC-derived CXCR6+ and CXCR6− NK cells both reduced viral replication, but CXCR6+ NK cells mediated significantly greater suppression. In HIV-infected humanized mice, weekly infusion of expanded PBMC-derived NK cells lowered plasma viral burden, with CXCR6+ NK cells providing stronger preservation of circulating CD4+ T cells and significant preservation of splenic CD4+ T cells. HIV-Env vaccination further enriched NK cells with enhanced therapeutic activity. CXCR6+ NK cells derived from HIV-Env–vaccinated humanized mice produced the strongest suppression of HIV replication and restored CD4+ T-cell frequencies in blood and spleen to levels comparable to uninfected controls. Together, these findings identify CXCR6+ NK cells as an HIV-responsive adaptive NK-cell subset that combines antiviral activity with preservation of CD4+ T-cell immunity in vivo. These data support further development of CXCR6+ NK-cell therapy as a vaccine-informed cellular immunotherapy strategy for HIV.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.