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Arango-Franco CA, Ogishi M, Unger S, Delmonte OM, Orrego JC, Yatim A, Velasquez-Lopera MM, Zea-Vera AF, Bohlen J, Chbihi M, Fayand A, Sánchez JP, Rojas J, Seeleuthner Y, Le Voyer T, Philippot Q, Payne KJ, Gervais A, Erazo-Borrás LV, Correa-Londoño LA, Cederholm A, Gallón-Duque A, Goncalves P, Doisne JM, Horev L, Charmeteau-de Muylder B, Álvarez JÁ, Arboleda DM, Pérez-Zapata L, Vásquez-Echeverri E, Moncada-Vélez M, López JA, Caicedo Y, Palterer B, Patiño PJ, Montoya CJ, Chaldebas M, Zhang P, Nguyen T, Ma CS, Jeljeli M, Alzate JF, Cabarcas F, Khan T, Rinchai D, Prétet JL, Boisson B, Generalized Verrucosis Japanese Consortium , Marr N, Ibrahim R, Molho-Pessach V, Boisson-Dupuis S, Kiritsi D, Barata JT, Landegren N, Neven B, Abel L, Lisco A, Béziat V, Jouanguy E, Bustamante J, Di Santo JP, Tangye SG, Notarangelo LD, Cheynier R, Natsuga K, Arias AA, Franco JL, Warnatz K, Casanova JL, Puel A
J. Clin. Invest. 134 (19) - [2024-10-01; online 2024-10-01]
Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.
Autoimmunity and Serology Profiling [Service]
PubMed 39352394
DOI 10.1172/JCI180251
Crossref 10.1172/JCI180251
pii: 180251
pmc: PMC11444196