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Published on: June 7, 2017
KLF2 determines the susceptibility of T cells to immunoregulatory NK cells
Stephen Waggoner1, Andrew Cox1, Laura Canaday1
1Cincinnati Children's Hospital Medical Center.
Abstract:
Natural killer (NK) cells suppress cellular and humoral immune responses via killing of T cells, resulting in diminished vaccine responses in mice and humans. Efforts to overcome this roadblock and achieve optimal immunity require an improved understanding of the molecular mediators facilitating NK cell-targeting of discrete subsets of CD4 T cells. We employed single-cell forensic victimology and CRISPR-Cas9 editing to delineate a transcriptional program uniquely responsible for the susceptibility of a subpopulation of CD4 T cells to perforin-dependent immunoregulation by NK cells. The unique vulnerability of these CD4 T cells relative to other subsets of CD4 T cells was not associated with a pattern of NK-cell-receptor ligand expression that would favor activation of NK cells. Instead, susceptible CD4 T cells were skewed toward follicular helper T cell (Tfh) differentiation and exhibited intermediate expression of Klf2 and a related suite of KLF2-target genes (e.g. S1pr1) involved in cell migration and spatial positioning. NK-cell dependent suppression of the subset of Tfh exhibiting intermediate expression of KLF2 and S1PR1 was confirmed with single-cell proteomics. CRISPR targeting of KLF2 in CD4 T cells prevented suppression by NK cells. Thus, KLF2 regulation of spatial positioning of T cells is a key determinant of NK-cell immunoregulatory function and a possible target for strategies to enhance vaccine efficacy.
Insights
Natural killer (NK) cells can suppress immune responses by targeting specific CD4 T cells. This study identifies KLF2 gene regulation of T cell positioning as a key factor in NK cell immune suppression, offering a target to improve vaccine efficacy.
Area of Science:
- Immunology
- Cell Biology
Background:
- Natural killer (NK) cells can inhibit immune responses by eliminating T cells, which negatively impacts vaccine effectiveness in both mice and humans.
- Understanding the molecular mechanisms by which NK cells target specific CD4 T cell subsets is crucial for enhancing immunity.
Purpose of the Study:
- To identify the molecular mediators responsible for NK cell-mediated suppression of CD4 T cells.
- To investigate the role of KLF2 in T cell susceptibility to NK cell immunoregulation.
Main Methods:
- Single-cell transcriptomics and CRISPR-Cas9 gene editing were used to identify key genes involved in NK cell targeting.
- Single-cell proteomics was employed to confirm NK cell-dependent suppression of specific T cell subsets.
- Analysis of KLF2 and KLF2-target gene expression in CD4 T cell subsets.
Main Results:
- A specific subpopulation of CD4 T cells, skewed towards follicular helper T cell (Tfh) differentiation, was found to be uniquely susceptible to NK cell-mediated suppression.
- This susceptibility was linked to intermediate expression of Klf2 and its target genes (e.g., S1pr1), which regulate cell migration and positioning, rather than NK cell activation patterns.
- CRISPR-mediated targeting of KLF2 in CD4 T cells abrogated NK cell-induced suppression.
Conclusions:
- KLF2-mediated regulation of T cell spatial positioning is a critical determinant of NK cell immunoregulatory function.
- Targeting KLF2 offers a potential strategy to enhance vaccine efficacy by preventing NK cell-mediated suppression of crucial T cell subsets.
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