Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury.

Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.

CD21-independent Epstein-Barr virus entry into NK cells.

Extranodal natural killer (NK)/T-cell lymphoma is an aggressive malignant disease that is associated with Epstein-Barr viral (EBV) infection. To date, the mechanism of viral entry into NK cells remains uncertain. Here, we investigated this mechanism using human NK cells in vitro. CD21 mRNA expression, an EBV-entry receptor, was transiently detected in NK cells after exosome treatment, and levels decreased after further culture. CD21 protein expression was also transiently transferred to NK cells after co-culture with an EBV-positive Burkitt lymphoma cell line (Raji) via trogocytosis. However, EBV did not infect NK cells through CD21-mediated trogocytosis. Unexpectedly, when NK cell leukemia cells, as well as primary NK cells, were treated with viral supernatant, EBV genes, but not RNA, were detected in the NK cells, at latency stage 0. Therefore, these results suggest that EBV-NK cell infection results from the direct transfer of viral episomes, independent of EBV-positive B cells.

Human group3 innate lymphoid cells express DR3 and respond to TL1A with enhanced IL-22 production and IL-2-dependent proliferation.

Death receptor 3 (DR3, TNFRSF25) is expressed by activated lymphocytes and signaling by its ligand, TL1A, enhances cytokine expression and proliferation. Recent studies show that DR3 is also present on murine type 2 innate lymphoid cells (ILC2s). Here, we show that DR3 is expressed by IL-22-producing human group 3 innate lymphoid cells (ILC3s). Stimulation of ILC3s with exogenous TL1A alone had no impact on cytokine production or proliferation. Addition of TL1A to IL-1ß + IL-23 significantly enhanced the amount IL-22 produced by ILC3s as well as the percentage IL-22- and IL-8-producing cells. Addition of TL1A to IL-1ß + IL-23 also augmented ILC3 proliferation. Mechanistically, this occurred through the upregulation of CD25 and responsiveness to IL-2 stimulation. The combination of TL1A, IL-1ß+ IL-23, and IL-2 expanded ILC3s while IL-1ß+ IL-23 did not increase proliferation above controls. After 2 weeks of expansion, ILC3s maintained their phenotype, transcription factor expression, and function (IL-22 production). These findings identify DR3 as a costimulatory molecule on ILC3s that could be exploited for ex vivo expansion and clinical use.

CD15+/CD16low human granulocytes from terminal cancer patients: granulocytic myeloid-derived suppressor cells that have suppressive function.

Myeloid-derived suppressor cells (MDSCs) are a subpopulation of myeloid cells with immunosuppressive function whose numbers are increased in conditions such as chronic infection, trauma, and cancer. Unlike murine MDSCs defined as CD11b(+)/Gr-1(+), there are no specific markers for human MDSCs. The goal of this study was to delineate a specific human MDSCs subpopulation in granulocytes from terminal cancer patients and investigate its clinical implications. Here, we show that the CD15(+)/CD16(low) subset was increased in terminal cancer patients compared with healthy donors (P = 0.009). Phorbol 12-myristate 13-acetate-activated granulocytes (CD16(low)/CD66b(++)/CD15(+)) that have a phenotype similar to MDSCs from cancer patients, effectively suppressed both proliferation and cytotoxicity of normal T cells. Among cancer patients, T-cell proliferation was highly suppressed by granulocytes isolated from terminal cancer patients with a high proportion of CD15(+)/CD16(low) cells. Patients with low peripheral blood levels of CD15(+)/CD16(low) cells had significantly longer survival than those with high levels (P = 0.0011). Patients with higher levels of CD15(+)/CD16(low) also tended to have poor performance status (P = 0.05). These data suggest that CD15(+)/CD16(low) granulocytes found in terminal cancer patients may play a role in the progression of cancer by inhibiting tumor immunity.