PTPN22 controls the interrelationship of IL-21+ and FOXP3+ CD4 T cells in T1D

PROJECT SUMMARY
Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing pancreatic beta cells. While
significant progress has been made in the past decades, our understanding of T1D pathogenesis remains far
from complete. Nonobese diabetic (NOD) mice develop spontaneous T1D and have been used extensively to
obtain mechanistic insight of this autoimmune disease. Pathogenic CD4 T cells promote T1D by secreting
inflammatory cytokines, enhancing the immunogenic functions of antigen presenting cells (APCs), and help
cytotoxic CD8 T cells that directly kill beta cells through the recognition of peptide-MHC I complexes.
Autoreactive T cells and APCs are controlled by FOXP3+ regulatory CD4 T cells (Tregs), and defects
associated with Tregs have been reported in T1D patients. Recently, a diabetogenic role of CD4 T cell-derived
interleukin (IL)-21 has emerged. IL-21 promotes T1D development in part through its ability to support the
survival and function of diabetogenic CD8 T cells. Interestingly, NOD islet-infiltrating IL-21+ CD4 T cells have
a unique phenotype distinct from those in lymphoid tissues. Importantly, NOD mice genetically rendered IL-21-
deficient are completely resistant to diabetes. Significantly higher frequencies of circulating IL-21+ CD4 T cells
have been found in subjects with beta-cell autoimmunity than in healthy controls, consistent with a role of IL-21
in promoting T1D development in humans. Collective results from both mouse and human studies strongly
indicate a central role of IL-21+ beta-cell autoreactive CD4 T cells in T1D pathogenesis. Both genetic
susceptibility and environmental factors contribute to T1D development. The PTPN22 R620W variant is one of
the top genetic risk factors that are associated with T1D development in humans. PTPN22 has been shown to
regulate cells within the innate and adaptive immune systems, but additional effort is needed to identify its
T1D-related function. NOD mice deficient in PTPN22 or carrying the 619W knock-in allele (orthologous to
human 620W) developed accelerated autoimmune diabetes compared to the wildtype control, consistent with
its role in T1D. Our preliminary results showed that Ptpn22-/- CD4 T cells were more diabetogenic than the
wildtype counterpart. We further demonstrated by flow cytometry and paired single-cell RNA sequencing
(scRNA-seq) and scTCR-seq that CD4 T cells were more prone to be IL-21+ effectors than Tregs in islets of
NOD.Ptpn22-/- mice, supporting a role of PTPN22 in their fate decision at the site of autoimmune destruction.
The overall hypothesis is that PTPN22 regulates T1D by controlling the balance of IL-21+ CD4 T cells and
FOXP3+ Tregs. We will determine if the balance of IL-21+ CD4 T cells and FOXP3+ Tregs is altered by the
Ptpn22 619W risk allele and mechanistically identify how PTPN22 controls the differentiation and accumulation
of IL-21+ CD4 T cells and FOXP3+ Tregs. By completing the proposed experiments, we will be able to provide
important insight into the role of PTPN22 in CD4 T cell fate decision.

Grant Number: 5R21AI180277-02
NIH Institute/Center: NIH
Principal Investigator: Yi-Guang Chen