Resolution Of Autoimmune Disease Research Articles

TIGIT+ A2Ar-Dependent anti-uveitic Treg cells are a novel subset of Tregs associated with resolution of autoimmune uveitis

Regulatory T cells (Tregs) are necessary to prevent autoimmune disease. As such, stable FoxP3 expression is required for the proper function of Tregs in the control of autoimmune disease. Different Treg subsets that utilize different mechanisms of suppression have been identified. The T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif (TIGIT) is a relatively new Treg cell marker that has a suppressive function. We have previously identified the adenosine 2A receptor (A2Ar) as a requirement for the emergence of Tregs following resolution of autoimmune disease. Using a FoxP3-GFP-Cre reporter mouse, we identify FoxP3 and ‘exFoxP3’ cells, show FoxP3 and not exFoxP3 cells are suppressive. We further show FoxP3 cells express TIGIT, and are induced through A2Ar in healthy volunteers, but not patients with autoimmune disease. Furthermore, we show Tregs emerge in the target tissue at the onset of autoimmune disease in an A2Ar-dependent manner. In summary, we identify a novel subset of TIGIT+ Tregs that are induced through stimulation of the A2Ar.

Regulation of CD8+regulatory T cells: Interruption of the NKG2A–Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease

Regulation of autoreactive CD4 T cells is essential to maintain self-tolerance and prevent autoimmune disease. Although CD8 T regulatory (Treg) cells that recognize self-peptides restricted by Qa-1 (HLA-E in humans) inhibit autoreactive CD4 cells and attenuate experimental autoimmune encephalomyelitis (EAE), the mechanism of this interaction is unclear. We generated Qa-1 mutant knock-in mice that impair Qa-1 binding to the T cell receptor (TCR) and CD94/NKG2A receptors. Analysis of these mice showed that TCR-dependent recognition of Qa-1-peptide complexes on target CD4 cells is essential for suppression by CD8 Treg cells. Further analysis revealed that genetic disruption of the Qa-1-CD94/NKG2A interaction unleashes robust CD8 Treg cell activity that completely abolishes development of EAE.

Female mice are more susceptible to developing inflammatory disorders due to impaired transforming growth factor β signaling in salivary glands

Transforming growth factor beta (TGFbeta) plays a key role in the onset and resolution of autoimmune diseases and chronic inflammation. The aim of this study was to delineate the precise function of TGFbeta signaling in salivary gland inflammation. We impaired TGFbeta signaling in mouse salivary glands by conditionally inactivating expression of TGFbeta receptor type I (TGFbetaRI), either by using mouse mammary tumor virus-Cre mice or by delivering adenoviral vector containing Cre to mouse salivary glands via retrograde infusion of the cannulated main excretory ducts of submandibular glands. TGFbetaRI-conditional knockout (TGFbetaRI-coko) mice were born normal; however, female TGFbetaRI-coko mice developed severe multifocal inflammation in salivary and mammary glands and in the heart. The inflammatory disorder affected normal growth and resulted in the death of the mice at ages 4-5 weeks. Interestingly, male TGFbetaRI-coko mice did not exhibit any signs of inflammation. The female TGFbetaRI-coko mice also showed an increase in Th1 proinflammatory cytokines in salivary glands and exhibited an up-regulation of peripheral T cells. In addition, these mice showed an atypical distribution of aquaporin 5 in their salivary glands, suggesting likely secretory impairment. Administration of an adenoviral vector encoding Cre recombinase into the salivary glands resulted in inflammatory foci only in the glands of female TGFbetaRI-loxP-flanked (floxed) mice (TGFbetaRI-f/f mice), but not in those of male and female wild-type mice or male TGFbetaRI-f/f mice. These results suggest that female mice are uniquely more susceptible to developing inflammatory disorders due to impaired TGFbeta signaling in their salivary glands.