Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis

Abstract

Pernicious anemia and gastric carcinoma are serious sequelae of autoimmune gastritis (AIG). Our study indicates that in adult C57BL/6 DEREG mice expressing a transgenic diphtheria toxin receptor under the Foxp3 promoter, transient Treg cell depletion results in long-lasting AIG associated with both H+K+ATPase and intrinsic factor autoantibody responses. Although functional Treg cells emerge over time during AIG occurrence, the effector T cells rapidly become less susceptible to Treg cell-mediated suppression. While previous studies have implicated dysregulated Th1 responses in AIG pathogenesis, eosinophils have been detected in gastric biopsies from patients with AIG. Indeed, AIG in DEREG mice is associated with strong Th2 responses, including dominant IgG1 autoantibodies, elevated serum IgE, increased Th2 cytokine production, and eosinophil infiltration in the stomach draining lymph nodes. Additionally, the stomachs exhibit severe mucosal and muscular hypertrophy, parietal cell loss, mucinous epithelial cell metaplasia, and massive eosinophilic inflammation. Notably, the Th2 responses and gastritis severity are significantly ameliorated in IL-4- or eosinophil-deficient mice. Furthermore, expansion of both Th2-promoting IRF4+PD-L2+ dendritic cells and ILT3+ rebounded Treg cells were detected after transient Treg cell depletion. Collectively, these data suggest that Treg cells maintain physiological tolerance to clinically relevant gastric autoantigens, and Th2 responses can be a pathogenic mechanism in autoimmune gastritis.

Regulatory T cells are required for normal and activin‐promoted wound repair in mice

“…The overexpression of IL‐4 together with IL‐5 in the absence of Tregs in mice is consistent with data obtained in a pulmonary infection model . Furthermore, Treg depletion caused severe autoimmune gastritis that was ameliorated by loss of IL‐4 . Interestingly, negative effects of increased levels of IL‐4 on wound healing have been described , suggesting that upregulation of this cytokine further contributes to the impaired healing in Treg‐depleted mice.…”

Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance

“…Thus, our findings also argue against another prevailing opinion, that systemic tolerance can only be initiated and maintained by MGCA present in the neonatal period (19). It should be noted that transiently Treg-depleted FOXP3-DTR mice or DEREG mice were also used to document a role for Tregs in tolerance for murine gastric autoantigens (57)(58)(59).…”

A Mutation in the Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells

“…The a-chain of the cytokine receptor IL-33R (St2 (legend continued on next page) or IL1RL1, interleukin 1 receptor-like 1) and the differentiation marker KLRG1, which are associated with GATA3 expression in Treg cell and Th2 cells (Delacher et al, 2017), were not upregulated in the M370I Treg cells compared to those in wild-type Tregs ( Figure 3F). M370I Treg cells also expressed high levels of CD85k, also known as ILT3 (immunoglobulin-like transcript 3) ( Figure 3G), a receptor discovered on a Treg subpopulation that promotes Th2 immune responses in vitro and in vivo by inducing the maturation of IRF4 + PD-L2 + dendritic cells (DCs) (Harakal et al, 2016;Ulges et al, 2015). Indeed, the M370I Tg mice presented an increased frequency of Th2-promoting IRF4 + PD-L2 + cells among the CD11c + MHCII + splenic DCs ( Figure 3G).…”