Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.

The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease.

NFIL3 contributes to cytotoxic T lymphocyte-mediated killing.

Cytotoxic T lymphocytes (CTLs) are key effectors of the adaptive immune system that recognize and eliminate virally infected and cancerous cells. In naive CD8 T cells, T-cell receptor (TCR) engagement drives a number of transcriptional, translational and proliferation changes over the course of hours and days leading to differentiation into CTLs. To gain a better insight into this mechanism, we compared the transcriptional profiles of naive CD8 T cells to those of activated CTLs.

Imaging the T-cell receptor: new approaches, new insights.

T cells recognize pathogenic antigens via the T-cell antigen receptor (TCR). This protein complex binds to antigen fragments on the surface of antigen-presenting cells. To understand how cellular activation can ensue rapidly from molecular recognition, the localization and distribution of the TCR on the surface of the resting T cell are of particular importance.

Targeting non-coding RNA family members with artificial endonuclease XNAzymes.

Non-coding RNAs (ncRNAs) offer a wealth of therapeutic targets for a range of diseases. However, secondary structures and high similarity within sequence families make specific knockdown challenging. Here, we engineer a series of artificial oligonucleotide enzymes (XNAzymes) composed of 2'-deoxy-2'-fluoro-β-D-arabino nucleic acid (FANA) that specifically or preferentially cleave individual ncRNA family members under quasi-physiological conditions, including members of the classic microRNA cluster miR-17~92 (oncomiR-1) and the Y RNA hY5.