Common variable immunodeficiency-associated endotoxemia promotes early commitment to the T follicular lineage
Le Coz, C., Bengsch, B., Khanna, C. et al.
Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numerical and/or functional T helper cell alterations. The causes, interrelationships and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia and/or autoantibody production remain unclear.
To determine how circulating CD4+ T-cells are altered in CVID subjects with autoimmune cytopenias (CVID+AIC) and the causes of these derrangements.
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, genetically diverse CVID subject cohort (n=69) 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 co-cultures and Treg suppression.
Whereas CD4+ T helper cell profiles from healthy donors and CVID subjects without autoimmune cytopenias were virtually indistinguishable, CVID+AIC T cells exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and ICOSL. The resulting enlarged CVID+AIC circulating Tfh (cTfh) cell population provided efficient help to receptive HD B cells but not unresponsive CVID B cells. Despite this, CVID+AIC cTfh exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with Treg suppression assays and were associated with autoantibody production.
Endotoxemia is associated with early commitment to the follicular T cell lineage in IgA-deficient CVID subjects, particularly those with AICs.
Le Coz, C., Bengsch, B., Khanna, C. et al. "Common variable immunodeficiency-associated endotoxemia promotes early commitment to the T follicular lineage" Journal of Allergy and Clinical Immunology (2019): doi: 10.1016/j.jaci.2019.08.007