ABSTRACT
Previous studies have identified a unique Treg population, which expresses the Th17 characteristic transcription factor RORγt. These RORγt+ Tregs possess enhanced immunosuppressive capacity, which endows them with great therapeutic potential. However, as a caveat, they are also capable of secreting pro-inflammatory IL-17A. Since the sum function of RORγt+ Tregs in glomerulonephritis (GN) remains unknown, we studied the effects of their absence. Purified CD4+ T cell populations, containing or lacking RORγt+ Tregs, were transferred into immunocompromised RAG1 knockout mice and the nephrotoxic nephritis model of GN was induced. Absence of RORγt+ Tregs significantly aggravated kidney injury, demonstrating overall kidney-protective properties. Analyses of immune responses showed that RORγt+ Tregs were broadly immunosuppressive with no preference for a particular type of T cell response. Further characterization revealed a distinct functional and transcriptional profile, including enhanced production of IL-10. Expression of the chemokine receptor CCR6 marked a particularly potent subset, whose absence significantly worsened GN. As an underlying mechanism, we found that chemokine CCL20 acting through receptor CCR6 signaling mediated expansion and activation of RORγt+ Tregs. Finally, we also detected an increase of CCR6+ Tregs in kidney biopsies, as well as enhanced secretion of chemokine CCL20 in 21 patients with anti-neutrophil cytoplasmic antibody associated GN compared to that of 31 healthy living donors, indicating clinical relevance. Thus, our data characterize RORγt+ Tregs as anti-inflammatory mediators of GN and identify them as promising target for Treg directed therapies.
Subject(s)
Glomerulonephritis , Nuclear Receptor Subfamily 1, Group F, Member 3 , Mice , Animals , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , T-Lymphocytes, Regulatory , Chemokine CCL20/genetics , Chemokine CCL20/metabolism , Kidney/pathology , Mice, Knockout , Th17 Cells , Receptors, CCR6/genetics , Receptors, CCR6/metabolismSubject(s)
Pemphigoid, Bullous , Humans , Non-Fibrillar Collagens , Dystonin , Autoantigens , Autoantibodies , Enzyme-Linked Immunosorbent AssayABSTRACT
Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP is characterized by the development of tense blisters induced by tissue-bound specific autoantibodies directed against the major autoantigens bullous pemphigoid autoantigen 180 (BP180, also called BPAG2 or Collagen XVII) and bullous pemphigoid autoantigen 230 (BP230, also called BPAG1 or dystonin). The vast majority of BP patients have autoantibodies targeting BP180, or both, BP180 and BP230. The hemidesmosomal protein BP180 is regarded as the main autoantigen, whereas the pathophysiologic relevance of intracellularly-located BP230 is controversial. A small subpopulation of BP patients selectively reveals autoantibodies against BP230 (BP230+ patients) strongly supporting that BP230 autoantibodies might be sufficient to induce skin pathology. In line, BP animal models have been developed, which successfully mimic a human BP phenotype by targeting BP230. In this context, our group has recently shown that a murine autoantibody targeting BP230 induces subepidermal blisters in vivo. This finding suggests that blister formation in the population of patients with selective autoreactivity against BP230 may share pathophysiologic features of pathogenic anti-BP230 autoantibodies in our murine model. This review summarizes the clinical features of BP patients with selective autoreactivity against BP230, enlightens the currently available BP mouse models targeting BP230 and discusses the potential pathophysiological mechanism of BP230 autoantibodies.
Subject(s)
Pemphigoid, Bullous , Animals , Autoantibodies , Autoantigens , Comprehension , Dystonin , Humans , Immunoglobulin G , Mice , Non-Fibrillar Collagens , Skin/pathologyABSTRACT
BACKGROUND: New therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown. METHODS: To learn more about the complex role of CD4+ T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell-specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations. RESULTS: Lack of IL-6Ra signaling in mouse CD4+ T cells impaired the generation of proinflammatory Th17 cells, but surprisingly did not ameliorate the course of GN. In contrast, renal damage was significantly reduced by restricting IL-6Ra deficiency to T effector cells and excluding Tregs. Detailed studies of Tregs revealed unaltered IL-10 production despite IL-6Ra deficiency. However, in vivo and in vitro, IL-6Ra classic signaling induced RORγt+Foxp3+ double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra-/- Tregs resulted in severe aggravation of GN in mice. CONCLUSIONS: Our data refine the old paradigm, that IL-6 enhances Th17 responses and suppresses Tregs. We here provide evidence that T cell-intrinsic IL-6Ra classic signaling indeed induces the generation of Th17 cells but at the same time highly immunosuppressive RORγt+ biTregs. These results advocate caution and indicate that IL-6-directed therapies for GN need to be cell-type specific.
