A Single Helper T Cell Clone Is Sufficient to Commit Polyclonal Naive B Cells to Produce Pathogenic IgG in Experimental Pemphigus Vulgaris

Abstract

The development of naive B cells into IgG-producing memory B cells requires cognate T cell-B cell interaction in Ag-specific immune responses. It is unknown whether a single T cell clone is sufficient or whether multiple clones are necessary to induce polyclonal IgG production in vivo. We addressed this issue using a mouse model of pemphigus vulgaris, a fatal autoimmune blistering skin disease caused by IgG autoantibodies against desmoglein (Dsg) 3. We previously isolated several Dsg3-reactive T cell clones from Dsg3−/− mice. Among these, two pathogenic T cell clones induced anti-Dsg3 IgG production and the development of a pemphigus phenotype when adoptively transferred with unprimed B cells from Dsg3−/− mice. IgG Abs harvested from recipient mice reacted with at least three parts of the extracellular domain of Dsg3, as determined using domain-swapped Dsg3/Dsg1 molecules. The anti-Dsg3 IgGs included at least two subclasses among IgG1, IgG2a, IgG2b, and IgG3 in each mouse. The anti-Dsg3 IgG induced by Dsg3-reactive T cell clones with primed B cells from Dsg3−/− mice also showed reactivity against different parts of the molecule, with a similar epitope distribution. Together, these results indicate that a single potent Dsg3-reactive T cell is sufficient to commit polyclonal naive B cells to produce pathogenic anti-Dsg3 IgG Abs and induce the PV phenotype. These findings provide an important framework for examining immunological mechanisms in Ab-mediated autoimmune diseases.

Th17 Cells Carrying TCR Recognizing Epidermal Autoantigen Induce Psoriasis-like Skin Inflammation

“…Our previous work indicates that epidermis-specific Th1 cells induce interface dermatitis, and epidermis-specific Th2 cells plus B cells induce autoantibody production (25). In this study, we showed that epidermis-specific Th17 cells induce psoriasis.…”

“…Seven of twenty T cell lines induced IgG anti-Dsg3 Ab production and acantholytic blister, a characteristic histological feature, in recipient mice. Th2-type differentiation was required for pathogenic Dsg3-reactive T cell lines to promote IgG anti-Dsg3 Ab production by primed B cells (25). Furthermore, we showed that interface dermatitis was developed in mice that were adoptively transferred with Dsg3-specific CD4 + T cells from Dsg3-specific TCR-tg mice or CD4 + T cells carrying retrovirally transduced Dsg3-specific TCR (26).…”

“…Previously, we reported a unique system evaluating the in vivo pathogenicity of desmoglein 3 (Dsg3)-reactive T cells at a clonal level in a mouse model for pemphigus vulgaris, an autoimmune blistering disease induced by anti-Dsg3 autoantibodies (24,25). Dsg3-reactive CD4 + T cell lines generated in vitro were adoptively transferred into Rag-2 2/2 mice with primed B cells derived from Dsg3-immunized Dsg3 2/2 mice.…”

B Cells, Dendritic Cells, and Macrophages Are Required To Induce an Autoreactive CD4 Helper T Cell Response in Experimental Epidermolysis Bullosa Acquisita

“…The latter can be in detail investigated by transfer of lymphocytes into immunodeficient mice; in these models, transferred lymphocytes are derived from mice lacking certain AIBD autoantigens or from animals immunized by skin grafting (14,15). Regarding the cellular requirements of autoantibody production, these models clearly documented a dependency on both B cells and CD4 T cells (15)(16)(17)(18). In principle, immunizationinduced models of AIBD (19)(20)(21) allow for investigating the cellular and molecular requirements that lead to loss of tolerance and subsequent autoantibody production.…”

Pathogenic IgG Antibodies against Desmoglein 3 in Pemphigus Vulgaris Are Regulated by HLA-DRB1*04:02–Restricted T Cells

“…The critical role of T cell-B cell interaction in the PV pathogenesis is also supported by a PV mouse model established by Amagai and coworkers (46,47 Moreover, using the same animal model, Takahashi et al (48) showed that a single Dsg3-reactive T cell clone was sufficient to prime naive B cells to produce Dsg3-specific pathogenic IgG autoantibodies. In an independent mouse model, immunization of mice with human Dsg3 led to the induction of Dsg3-reactive Th2 cells that were able to render unprimed B cells to secrete antiDsg3 IgG (49).…”