Expansion of Th17 Cells and Functional Defects in T Regulatory Cells Are Key Features of the Pancreatic Lymph Nodes in Patients With Type 1 Diabetes

Abstract

OBJECTIVEAutoimmune diseases, including type 1 diabetes, are thought to have a Th17-cell bias and/or a T-regulatory cell (Treg) defect. Understanding whether this is a hallmark of patients with type 1 diabetes is a crucial question that is still unsolved, largely due to the difficulties of accessing tissues targeted by the disease.RESEARCH DESIGN AND METHODSWe phenotypically and functionally characterized Th17 cells and Tregs residing in the pancreatic-draining lymph nodes (PLNs) of 19 patients with type 1 diabetes and 63 nondiabetic donors and those circulating in the peripheral blood of 14 type 1 diabetic patients and 11 healthy subjects.RESULTSWe found upregulation of Th17 immunity and functional defects in CD4+CD25bright Tregs in the PLNs of type 1 diabetic subjects but not in their peripheral blood. In addition, the proinsulin-specific Treg-mediated control was altered in the PLNs of diabetic patients. The dysfunctional Tregs isolated from diabetic subjects did not contain contaminant effector T cells and were all epigenetically imprinted to be suppressive, as defined by analysis of the Treg-specific demethylated region within the forkhead box P3 (FOXP3) locus.CONCLUSIONSThese data provide evidence for an unbalanced immune status in the PLNs of type 1 diabetic subjects, and treatments restoring the immune homeostasis in the target organ of these patients represent a potential therapeutic strategy.

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

“…Moreover, circulating IL-17 + and beta cell-specific autoreactive CD4 + cells are present in the circulation of type 1 diabetes patients at diagnosis [16,17] and are associated with diabetes in NOD mice [18]. Importantly, increased expression of IL-17A was detected in the islets of a recently diagnosed type 1 diabetic patient [17] and increased numbers of Th17 cells are present in pancreatic lymph nodes of patients with long-term type 1 diabetes [19]. IL-17A enhances IL-1β+IFN-γ-or TNF-α+IFN-γ-induced apoptosis in rodent and human beta cells [16,17,20] and IL-1β+IFN-γ upregulates the expression of the beta cell IL-17A receptor via the transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription (STAT) 1 [17].…”

“…Recent studies indicate an increased presence of Th17 cells among circulating T cells and in the pancreatic islets of type 1 diabetes patients [16][17][18][19]. Th17 cells secrete the cytokine IL-17A, which we and others have shown to exacerbate IL-1β+IFN-γ-and TNF-α+IFN-γ-induced apoptosis in MIN6 cells and human islets [16,17].…”

Interindividual variation in human T regulatory cells

“…Whether Tregs from T1D patients are dysfunctional is controversial (30,32,(34)(35)(36)(37), and it is possible that only one facet of their activity is altered (38). Recent results also suggest that, in T1D patients, effector T cells may be refractory to inhibition by Treg cells (39,40) although this point has also been debated (30,38).…”

“…It is now recognized that the frequency of FOXP3 + Treg cells in the blood of human T1D patients is comparable with that of healthy subjects (30)(31)(32), as in NOD mice (29,33). Whether Tregs from T1D patients are dysfunctional is controversial (30,32,(34)(35)(36)(37), and it is possible that only one facet of their activity is altered (38).…”

“…Some of the T1D susceptibility loci uncovered by large genome-wide association studies (GWASs) may plausibly influence Treg activity (e.g., IL2RA, IL2, CTLA4) (28). One can hypothesize that programmed Treg defects render an individual globally more susceptible to unrestrained activity of autoreactive cells or that Treg deficiencies occurring locally in the target organ, perhaps in response to environmental or infectious triggers, destabilize the local Treg/effector T equilibrium and allow terminal organ damage (29,30).…”