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Killer cell immunoglobulin-like receptors delineate distinct phenotypes and functions in human γδ T cells [ATAC]

ABSTRACT: Killer cell immunoglobulin-like receptors (KIRs) are a diverse family of HLA class I-specific receptors that shape immune responses, primarily through NK cells. Beyond NK cells, subsets of T cells, notably γδ T cells, express KIRs, but their roles remain unclear. Here, we demonstrate that KIR⁺γδ T cells are significantly more abundant in CMV-seropositive healthy adults, particularly within the Vδ2⁻ subset. These cells exhibit a TEMRA phenotype, are predominantly CD16⁺CD57⁺, hallmarks of a highly differentiated state, and express multiple NK cell-associated receptors. KIR+γδ T cells display enhanced cytotoxic potential, with higher levels of granzyme B and perforin than their KIR- counterparts. Using Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and transcriptional analyses, we show that KIR- and KIR+ γδ T cells reveal distinct molecular signatures, with KIR+γδ T cells transcriptionally and epigenetically aligning with terminally differentiated effector memory T cells, while KIR- cells retain a naïve-like phenotype. These findings suggest that CMV infection drives the differentiation of γδ T cells into potent, KIR-expressing cytotoxic effectors. This adaptive mechanism may bolster immune defense while maintaining self-tolerance, highlighting a previously unappreciated role for KIRs in shaping γδ T cell immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301798 | GEO | 2026/03/24

REPOSITORIES: GEO

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Project description:Our team had previously explored the potential of expanding cord blood (CB) derived γδ T cells (CB-gdT) as well as their corresponding ability to target primary acute myeloid leukemia (AML) cells. Using a feeder cell line-based in vitro expansion protocol, we achieved a clinically relevant scale expansion of γδ T cells over a period of 14 days. These cells exhibit variable degree of potency against a range of human AML cell lines and primary patient samples. In order to dissect the cellular and molecular programs governing the activation, differentiation and functional states of our in vitro expanded CB-gdT, we performed multiplex single cell sequencing analysis using the 10X Genomics Chromium System. After initial quality check and filtering, data from a total of 4,276 cells were retrieved. Among which, we identified 742 unique TCRγδ clonotypes, representing 18.6% of the starting 4,000 FACS purified γδ T cells seeded for expansion. Consistent to our FACS analysis, Vδ1 is the predominant TRD chain in the expanded cultures, accounting for 61.2% of all clones. Based on uniform manifold approximation and projection for dimension reduction (UMAP), all cells were clustered into 11 subsets. Key cytotoxic genes including GZMB, GZMA and NKG7 were all highly expressed across all clusters, indicating that the expanded cells were indeed functionally cytotoxic. Comparing against multiple curated gene sets, we have identified 3 main subsets of γδ T cells: the Proliferative, Cytotoxic γδ T cells (P-CT), Differentiated Cytotoxic γδ T cells (D-CT) and Late Activated Cytotoxic γδ T cells (LA-CT). P-CT (~46% of all cells) shows an expression profile positively associated with cell proliferation as well as increased cell surface expression of memory T cell markers CD27, CCR7 and CD62L. Similar to cytotoxic genes, genes associated with TCR signaling and interferon response were found to be expressed across all cell clusters, yet with elevated levels in D-CT and LA-CT. Furthermore, cell surface expression of different NK receptors including NKG2D, DNAM1 and NKp30 are more enriched in LA-CT compared to the other 2 subsets, suggesting the acquisition of additional NK receptor related functions in this group of cells. Consistent with the concept of progressive γδ T cell differentiation and activation in culture, we found that in 85 (11.5%) of the γδ T cell clones bearing more than 10 cells each, all clones contain cells distributed across the 3 different γδ T cell subsets. This is the first report on single cell immune profiling of in vitro expanded gdT cells derived from human CB.

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Killer cell immunoglobulin-like receptors delineate distinct phenotypes and functions in human γδ T cells [ATAC]

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