PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of
Florian Wiede1, Faruk Sacirbegovic1, Yew Ann Leong1
1Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia.
Abstract:
Non-coding single nucleotide polymorphisms that repress PTPN2 expression have been linked with the development of type 1 diabetes, rheumatoid arthritis and Crohn's disease. PTPN2 attenuates CD8+ T cell responses to self and prevents overt autoreactivity in the context of T cell homeostasis and antigen cross-presentation. The role of PTPN2 in other immune subsets in the development of autoimmunity remains unclear. Here we show that the inducible deletion of PTPN2 in hematopoietic compartment of adult non-autoimmune prone mice results in systemic inflammation and autoimmunity. PTPN2-deficient mice had increased inflammatory monocytes, B cells and effector T cells in lymphoid and non-lymphoid tissues and exhibited symptoms of dermatitis, glomerulonephritis, pancreatitis and overt liver disease. Autoimmunity was characterised by the formation of germinal centers in the spleen and associated with markedly increased germinal center B cells and T follicular helper (Tfh) cells and circulating anti-nuclear antibodies, inflammatory cytokines and immunoglobulins. CD8+ T cell proliferative responses were enhanced, and interleukin-21-induced STAT-3 signalling in Tfh cells and B cells was increased and accompanied by enhanced B cell proliferation ex vivo. These results indicate that deficiencies in PTPN2 across multiple immune lineages, including naive T cells, Tfh cells and B cells, contribute to the development of autoimmunity.
Insights
The protein tyrosine phosphatase non-protein-coding RNA 2 (PTPN2) is crucial for preventing autoimmunity. Its deficiency in immune cells triggers systemic inflammation and autoimmune disease across multiple organs.
Area of Science:
- Immunology
- Autoimmunity
- Molecular Biology
Background:
- Non-coding single nucleotide polymorphisms repressing PTPN2 expression are associated with autoimmune diseases like type 1 diabetes, rheumatoid arthritis, and Crohn's disease.
- PTPN2 plays a role in regulating CD8+ T cell responses and preventing autoreactivity within T cell homeostasis.
- The function of PTPN2 in other immune cell types concerning autoimmunity development is not fully understood.
Purpose of the Study:
- To investigate the role of PTPN2 in the hematopoietic compartment in the development of systemic inflammation and autoimmunity.
- To determine the impact of PTPN2 deficiency on various immune cell populations and their functions.
Main Methods:
- Inducible deletion of PTPN2 in the hematopoietic compartment of adult mice.
- Analysis of immune cell populations in lymphoid and non-lymphoid tissues.
- Assessment of autoimmune symptoms, autoantibodies, cytokines, and immunoglobulins.
- Evaluation of T cell proliferation and signaling pathways (STAT-3) in T follicular helper (Tfh) and B cells.
Main Results:
- Inducible PTPN2 deletion in mice led to systemic inflammation and multi-organ autoimmune disease.
- PTPN2-deficient mice exhibited increased inflammatory monocytes, B cells, and effector T cells.
- Autoimmunity was characterized by germinal center formation, increased B cells and Tfh cells, autoantibodies, and elevated cytokines.
- Enhanced CD8+ T cell proliferation and increased IL-21-induced STAT-3 signaling in Tfh and B cells were observed, leading to heightened B cell proliferation.
Conclusions:
- PTPN2 deficiency across multiple immune lineages, including naive T cells, Tfh cells, and B cells, contributes to the development of autoimmunity.
- PTPN2 is essential for maintaining immune homeostasis and preventing autoreactivity in various immune cell types.
- Loss of PTPN2 function can precipitate systemic inflammation and diverse autoimmune manifestations.
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