Common variable immunodeficiency–associated endotoxemia promotes early commitment to the T follicular lineage - 05/12/19
Abstract |
Background |
Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear.
Objective |
We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements.
Methods |
Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression.
Results |
Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency–associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production.
Conclusions |
Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Common variable immunodeficiency, autoimmune cytopenias, activin A, endotoxin, follicular helper T cell, regulatory T cell, recent thymic emigrant, time-of-flight cytometry
Abbreviations used : AIC, AIHA, CFSE, CSR, cTFH, CVID, CVID+AIC, CVID−AIC, CyTOF, ES, FACS, FOXP3, HD, ICOS, ICOSL, ITP, PD-1, RTE, TFH, TLR, Treg, t-SNE
Plan
| Supported by grant numbers K23AI115001 (to N.R.), AI146026 (to N.R.), AI105343 (to E.J.W.), AI108545 (to E.J.W.), and AI117950 (to E.J.W.) from the National Institutes of Health/National Institute of Allergy and Infectious Diseases; grant CA210944 from the National Institutes of Health/National Cancer Institute (to E.J.W.); grant number K12HD043245 from the National Institutes of Health/National Institute of Child Health and Human Development (to S.E.H.); the American Association of Allergy, Asthma & Immunology Foundation (to S.E.H.); the David and Hallee Adelman Immunotherapy Research Fund (to E.J.W.); the Parker Institute for Cancer Immunotherapy Bridge Scholar Award to (E.J.W.); and the Jeffrey Modell Foundation (to N.R.). |
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| Disclosure of potential conflict of interest: E. J. Wherry is a member of the Parker Institute for Cancer Immunotherapy which supported the UPenn cancer immunotherapy program; has consulting agreements with and/or is on the scientific advisory board for Merck, Roche, Pieris, Elstar, and Surface Oncology; is a founder of Arsenal Biosciences; and has a patent licensing agreement on the PD-1 pathway with Roche/Genentech. The rest of authors declare that they have no relevant conflicts of interest. |
Vol 144 - N° 6
P. 1660-1673 - décembre 2019 Retour au numéro
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