miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity

Abstract

Aberrant immune activation mediated by T effector cell populations is pivotal in the onset of autoimmunity in type 1 diabetes (T1D). T follicular helper (TFH) cells are essential in the induction of high-affinity antibodies, and their precursor memory compartment circulates in the blood. The role of TFH precursors in the onset of islet autoimmunity and signaling pathways regulating their differentiation is incompletely understood. Here, we provide direct evidence that during onset of islet autoimmunity, the insulin-specific target T-cell population is enriched with a C-X-C chemokine receptor type 5 (CXCR5)+CD4+ TFH precursor phenotype. During onset of islet autoimmunity, the frequency of TFH precursors was controlled by high expression of microRNA92a (miRNA92a). miRNA92a-mediated TFH precursor induction was regulated by phosphatase and tension homolog (PTEN) - phosphoinositol-3-kinase (PI3K) signaling involving PTEN and forkhead box protein O1 (Foxo1), supporting autoantibody generation and triggering the onset of islet autoimmunity. Moreover, we identify Krueppel-like factor 2 (KLF2) as a target of miRNA92a in regulating human TFH precursor induction. Importantly, a miRNA92a antagomir completely blocked induction of human TFH precursors in vitro. More importantly, in vivo application of a miRNA92a antagomir to nonobese diabetic (NOD) mice with ongoing islet autoimmunity resulted in a significant reduction of TFH precursors in peripheral blood and pancreatic lymph nodes. Moreover, miRNA92a antagomir application reduced immune infiltration and activation in pancreata of NOD mice as well as humanized NOD Scid IL2 receptor gamma chain knockout (NSG) human leucocyte antigen (HLA)-DQ8 transgenic animals. We therefore propose that miRNA92a and the PTEN-PI3K-KLF2 signaling network could function as targets for innovative precision medicines to reduce T1D islet autoimmunity.

A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes

“…Accordingly, children with long-term autoimmunity phenotypes show an accumulation of protective genotypes in T1D susceptibility genes (37), most notably, IL-2 , IL2-R α, INS VNTR , and IL-10 . In line, such children with long-term autoimmunity harbored T FH precursor cell frequencies as low as autoantibody-negative children (13), accompanied by an increase in insulin-specific T regs (12). …”

“…Ex vivo frequencies of human leukocyte antigen (HLA)–DQ8–restricted insulin-specific T regs were critically reduced during islet auto-immunity onset or in children with a fast progression to clinical T1D (12), accompanied by an increase in insulin-specific T follicular helper (T FH ) precursor cells (13). In contrast, high frequencies of insulin-specific T regs were associated with profound delays in progressing to symptomatic T1D (12).…”

Follicular helper T cells in type 1 diabetes

“…46,47 All these antibodies are secreted by longlived plasma cells, which are considered to be generated from GCs with the help of Tfh cells, suggesting the aberrant differentiation and function of Tfh cells in T1D patients. 50 It is worthy to note that the frequencies of insulin-specific Tfh precursor cells in children with the long-standing islet autoimmunity were significantly lower than those in new-onset children, 50 which could be a reflection of a decline of β cell numbers and diminished autoimmunity during the disease progression. 48 Examination of Tfh cells in newly diagnosed (within 1 week) T1D children and autoantibody-positive children with impaired glucose tolerance (IGT) showed that the frequency of circulating activated Tfh (CXCR5 + PD-1 + ICOS + ) cells was significantly higher, when compared with those in antibody-negative children and autoantibody-positive euglycemia children.…”

“…On the one hand, T cell development in T1D patients is distorted. 50 On the other hand, during the progression of the disease, self-antigens, especially those in the pancreas, are abundantly released from the damaged β cells and presented by APCs, resulting in the elevated T cell activation in the pancreatic lymph node by epitope spreading. 61,62 The immunorepertoire of complementaritydetermining region 3s (CDR3) in β chains of peripheral T cells was shorter when compared with those in healthy controls, which might increase the binding capacity of self-antigens and further T1D predisposition.…”

“…The mutation in Roquin (Roquin san ), which causes the substitution from methionine 199 (199M) to arginine (199R), fails to inhibit ICOS expression, resulting in the increased Tfh cell numbers. 50 60 The elevated abundance of micro RNA (miRNA) 92a is correlated with islet autoimmunity.…”