Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations
JOURNAL OF EXPERIMENTAL MEDICINE, vol.213, no.11, pp.2413-2435, 2016 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 213 Issue: 11
- Publication Date: 2016
- Doi Number: 10.1084/jem.20160576
- Journal Name: JOURNAL OF EXPERIMENTAL MEDICINE
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Page Numbers: pp.2413-2435
- Istanbul University Affiliated: No
Abstract
Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4(+) T cells are reduced. Their CD4(+) T cells do not respond to CD28 stimulation. Their CD4(+) T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells fail to activate NF-kappa B upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.