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Human cytomegalovirus expands a T cell population with loss of BCL11B expression and gain of NK cell identity

ABSTRACT: CD8+ T cells, critical mediators of adaptive immunity, may also exhibit innate-like properties, such as surface expression of NKG2C, an activating receptor typically associated with natural killer (NK) cells. We demonstrate that, similar to NK cells, NKG2C+TCRαβ+CD8+ T cells are associated with prior HCMV exposure. In addition to expressing several NK cell markers (CD56, KIR), NKG2C+CD8+ T cells are oligoclonal and do not upregulate PD1 despite chronic activation. Furthermore, NKG2C+CD8+ T cells from some individuals exhibit high effector function against leukemia cells and HCMV-infected fibroblasts, dictated by NKG2C and TCR specificity. Importantly, we observe that co-triggering of CD3 and NKG2C results in increased degranulation and IFN-γ production by NKG2C+CD8+ T cells in an additive fashion. Transcriptomic analysis reveals that the transcription factor BCL11B, a regulator of T cell developmental fate, is significantly down-modulated in NKG2C+CD8+ T cells when compared to conventional NKG2C-CD8+ T cells. BCL11B deletion in conventional CD8 T cells results in the emergence of a CD56+CD94+DAP12+NKG2C+CD45RA+CCR7-PD1-/low T cell population with activity against HLA-E+ targets. Given their intrinsic capacity to recognize diseased cells coupled with lack of PD-1 upregulation despite chronic stimulation, NKG2C+CD8+ T cells represent a novel lymphocyte population that straddles the boundary between innate and adaptive immunity, presenting an attractive alternative for cellular therapy, including CAR T-based therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179981 | GEO | 2021/10/14

REPOSITORIES: GEO

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Project description:Previous research on adaptive NK cells in rhesus macaques suffered from the lack of specific antibodies to differentiate between inhibitory CD94/NKG2A and stimulatory CD94/NKG2C heterodimeric receptors. Recently we reported an expansion of NKG2C receptor-encoding genes in rhesus macaques, but their expression and functional role on primary NK cells remained unknown due to this deficit. Thus, we established monoclonal antibodies 4A8 and 7B1 which show identical specificities and bind to both NKG2C-1 and NKG2C-2 but neither react with NKG2C-3 nor NKG2A on transfected cell lines. Using a combination of 4A8 and Z199 antibodies in multicolor flow cytometry we detected broad expression (4-73%) of NKG2C-1 and/or NKG2C-2 (NKG2C-1/2) on primary NK cells in rhesus macaques from our breeding colony. Stratifying our data to CMV-positive and CMV-negative animals, we noticed a higher proportion (23-73%) in primary NK cells expressing NKG2C-1/2 in CMV+ as compared to CMV- macaques (4-5%). These NKG2C-1/2-positive NK cells in CMV+ macaques are characterized by lower expression of IL12RB2, ZBTB16 and SH2D1B as well as high expression of IFN-gamma, indicating that antibody 4A8 detects CMV-associated adaptive NK cells. Single cell RNA seq data of 4A8-positive NK cells from a CMV-positive individual demonstrated that a high proportion of these adaptive NK cells transcribe in addition to NKG2C-1/2 also NKG2C-3, but interestingly NKG2A as well. Remarkably, NKG2C-1 and in particular NKG2C-2 have a higher affinity to Mamu-E as compared to NKG2A. Primary NK cells exposed to Mamu-E-expressing target cells displayed strong degranulation as well as IFN-gamma expression of 4A8+ adaptive NK cells of rhCMV+ animals that was not evident in rhCMV- animals. Thus, despite co-expression of inhibitory and stimulatory CD94/NKG2 receptors the higher number of different stimulatory NKG2C receptors and their higher binding avidity to Mamu-E outreach inhibitory signaling via NKG2A. These data demonstrate the evolutionary conservation of the CMV-driven development of NKG2C-positive adaptive NK cells with particular molecular signatures in primates and with changes in gene copy numbers and regulation and in ligand binding strength of NKG2C isotypes. Thus, rhesus macaques represent a suitable and valuable nonhuman primate animal model to study the CMV-NKG2C liaison in vivo.

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Human cytomegalovirus expands a T cell population with loss of BCL11B expression and gain of NK cell identity

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