TY - JOUR
T1 - Common variable immunodeficiency–associated endotoxemia promotes early commitment to the T follicular lineage
AU - Le Coz, Carole
AU - Bengsch, Bertram
AU - Khanna, Caroline
AU - Trofa, Melissa
AU - Ohtani, Takuya
AU - Nolan, Brian E.
AU - Henrickson, Sarah E.
AU - Lambert, Michele P.
AU - Kim, Taylor Olmsted
AU - Despotovic, Jenny M.
AU - Feldman, Scott
AU - Fadugba, Olajumoke O.
AU - Takach, Patricia
AU - Ruffner, Melanie
AU - Jyonouchi, Soma
AU - Heimall, Jennifer
AU - Sullivan, Kathleen E.
AU - Wherry, E. John
AU - Romberg, Neil
N1 - Funding Information:
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.).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.
Publisher Copyright:
© 2019 American Academy of Allergy, Asthma & Immunology
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - Common variable immunodeficiency
KW - activin A
KW - autoimmune cytopenias
KW - endotoxin
KW - follicular helper T cell
KW - recent thymic emigrant
KW - regulatory T cell
KW - time-of-flight cytometry
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UR - http://www.scopus.com/inward/citedby.url?scp=85072757778&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2019.08.007
DO - 10.1016/j.jaci.2019.08.007
M3 - Article
C2 - 31445098
AN - SCOPUS:85072757778
SN - 0091-6749
VL - 144
SP - 1660
EP - 1673
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 6
ER -