Common variable immunodeficiency–associated endotoxemia promotes early commitment to the T follicular lineage
In: Journal of Allergy and Clinical Immunology, Jg. 144 (2019-12-01), S. 1660-1673
Online
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Zugriff:
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.
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Common variable immunodeficiency–associated endotoxemia promotes early commitment to the T follicular lineage
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Autor/in / Beteiligte Person: | Taylor Olmsted Kim ; Romberg, Neil ; E. John Wherry ; Takach, Patricia ; Heimall, Jennifer ; Ohtani, Takuya ; Sullivan, Kathleen E. ; Feldman, Scott ; Fadugba, Olajumoke ; Khanna, Caroline ; Trofa, Melissa ; Lambert, Michele P. ; Jyonouchi, Soma ; Despotovic, Jenny M. ; Ruffner, Melanie A. ; Henrickson, Sarah E. ; Bengsch, Bertram ; Nolan, Brian E. ; Carole Le Coz |
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Zeitschrift: | Journal of Allergy and Clinical Immunology, Jg. 144 (2019-12-01), S. 1660-1673 |
Veröffentlichung: | Elsevier BV, 2019 |
Medientyp: | unknown |
ISSN: | 0091-6749 (print) |
DOI: | 10.1016/j.jaci.2019.08.007 |
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