Deep Analysis of Desmoglein-3-Reactive CD4+ T Cells in Pemphigus Vulgaris Reveals a Type 17/Type 2 T-Cell Signature.

Pemphigus vulgaris (PV) is an autoimmune blistering disorder that is caused by the loss of desmosomal cell-cell adhesion, initiated by the binding of IgG antibodies against the desmosomal components desmoglein (DSG)1 and DSG3. DSG3-reactive CD4+ T helper (Th) cells, in particular follicular Th cells, play a central role in autoantibody production by DSG3-specific B cells. In this study, we challenged the concept that distinct DSG3-reactive CD4+ T-cell subsets are critical in PV pathogenesis, utilizing phenotypical and functional state-of-the-art ex vivo assays. Using HLA class II-tetramer staining and activation-induced marker assay, we found an overall increase of circulating follicular Th and peripheral Th cells, another subset with the capacity to promote autoantibody production by B cells, in patients with PV compared with those in healthy controls. Within the DSG3-reactive T-cell population, Th17/circulating follicular Th17/peripheral Th17 cells represented the dominant subset, followed by a Th2/circulating follicular Th2/peripheral Th2-like cell signature. Upon ex vivo stimulation with overlapping peptides of DSG3, we found both an activated IL-17-producing CD4+ T-cell subset and an increased frequency of CD4+ T cells producing IL-21 in active PV. In summary, our findings demonstrate a preponderance of autoreactive type 17 and type 2 T-cell subsets in PV, which may serve as therapeutic targets.