Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 11, Pages 2413-2435Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160576
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Funding
- Institut National de la Sante et de la Recherche Medicale
- Paris Descartes University
- French National Research Agency (ANR) under the Investments for the Future Program [ANR-10-IAHU-01]
- National Agency for Research on AIDS and Viral Hepatitis (ANRS) [ANRS-13292]
- Rockefeller University
- St. Giles Foundation
- ANRS [13318]
- National Institute of Allergy and Infectious Diseases [5T32AI007512, R01AI100887-01]
- ANR [ANR-13-PDOC-0025-01]
- National Health and Medical Research Council of Australia
- Australian-American Fulbright Commission
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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.
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