Non-apoptotic TRAIL function modulates NK cell activity during viral infection.

The role of death receptor signaling for pathogen control and infection-associated pathogenesis is multifaceted and controversial. Here, we show that during viral infection, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) modulates NK cell activity independently of its pro-apoptotic function. In mice infected with lymphocytic choriomeningitis virus (LCMV), Trail deficiency led to improved specific CD8+ T-cell responses, resulting in faster pathogen clearance and reduced liver pathology. Depletion experiments indicated that this effect was mediated by NK cells. Mechanistically, TRAIL expressed by immune cells positively and dose-dependently modulates IL-15 signaling-induced granzyme B production in NK cells, leading to enhanced NK cell-mediated T cell killing. TRAIL also regulates the signaling downstream of IL-15 receptor in human NK cells. In addition, TRAIL restricts NK1.1-triggered IFNγ production by NK cells. Our study reveals a hitherto unappreciated immunoregulatory role of TRAIL signaling on NK cells for the granzyme B-dependent elimination of antiviral T cells.

Effect of patient positioning on toe pressure measurement using noninvasive vascular testing.

OBJECTIVE: Interpretation of digital pressure in the assessment of healing potential for diabetic foot disease has become common because of the potential for false elevation with the ankle-brachial index. However, the specific testing protocol for segmental Doppler examinations and photoplethysmography require patients to be in the supine position, with the lower limbs at heart level, in order to minimise the effect of hydrostatic pressure. This may be difficult in many patients with lower extremity pathology, particularly those who are nonambulatory, with painful wounds, or with orthopnea. In these situations, the noninvasive vascular test may be performed with the patient in a more comfortable position, which may include sitting in a wheelchair with the leg in a dependent position. The objective of this investigation was to evaluate the effect of patient positioning on measurement of the digital pressure. METHOD: Hallux pressures were measured in 20 healthy volunteers in 3 variable positions of limb dependency. RESULTS: The mean±standard deviation of digital pressure for subjects while lying supine with the limb at heart level was 103.5±26.0 mmHg (the recommended position for performance of the test), while sitting upright with the limb level on the table was 130.6±27.9 mmHg (+26.2%, p<0.0001) and sitting upright with the limb in a dependent position was 169.8±30.8 mmHg (+64.1%, p<0.0001). CONCLUSION: On the basis of these results, we conclude that patient positioning has a significant effect on measurement of digital pressure.

Immune checkpoint activity regulates polycystic kidney disease progression.

Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8+ T cells and slow tumor growth. We have previously shown that in PKD, CD8+ T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models (Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and programmed cell death ligand 1 (PD-L1)/CD80 on macrophages and epithelial cells in Pkd1RC/RC mice versus WT, paralleling disease severity. PD-L1/CD80 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti-PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti-PD-1 plus anti-CTLA-4, blocking 2 immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD severity. Combination therapy resulted in increased kidney CD8+ T cell numbers/activation and decreased kidney regulatory T cell numbers correlative with PKD severity. Together, our data suggest that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.