Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease.

The nature of gut intraepithelial lymphocytes (IELs) lacking antigen receptors remains controversial. Herein we showed that, in humans and in mice, innate intestinal IELs expressing intracellular CD3 (iCD3(+)) differentiate along an Id2 transcription factor (TF)-independent pathway in response to TF NOTCH1, interleukin-15 (IL-15), and Granzyme B signals. In NOTCH1-activated human hematopoietic precursors, IL-15 induced Granzyme B, which cleaved NOTCH1 into a peptide lacking transcriptional activity. As a result, NOTCH1 target genes indispensable for T cell differentiation were silenced and precursors were reprogrammed into innate cells with T cell marks including intracellular CD3 and T cell rearrangements. In the intraepithelial lymphoma complicating celiac disease, iCD3(+) innate IELs acquired gain-of-function mutations in Janus kinase 1 or Signal transducer and activator of transcription 3, which enhanced their response to IL-15. Overall we characterized gut T cell-like innate IELs, deciphered their pathway of differentiation and showed their malignant transformation in celiac disease.

Effects of hearing loss, age, noise exposure, and listening skills on envelope regularity discrimination.

The envelope regularity discrimination (ERD) test assesses the ability to discriminate irregular from regular amplitude modulation (AM). The measured threshold is called the irregularity index (II). It was hypothesized that the II at threshold should be almost unaffected by the loudness recruitment that is associated with cochlear hearing loss because the effect of recruitment is similar to multiplying the AM depth by a certain factor, and II values depend on the amount of envelope irregularity relative to the baseline modulation depth. To test this hypothesis, the ERD test was administered to 60 older adults with varying degrees of hearing loss, using carrier frequencies of 1 and 4 kHz. The II values for the two carrier frequencies were highly correlated, indicating that the ERD test was measuring a consistent characteristic of each subject. The II values at 1 and 4 kHz were not significantly correlated with the audiometric thresholds at the corresponding frequencies, consistent with the hypothesis. The II values at 4 kHz were significantly positively correlated with age. There was an unexpected negative correlation between II values and a measure of noise exposure. This is argued to reflect the confounding effects of listening skills.