PD-1 deletion restores susceptibility to experimental autoimmune encephalomyelitis in miR-155-deficient mice
1Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies 1420, Belgium Department of Clinical Microbiology and Immunology, College of Medical Laboratory Science, Third Military Medical University, Chongqing 400038, People's Republic of China.
Abstract:
MiR-155 (-/-) mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), while Pdcd1 (-/-) mice develop a more severe form of the disease. To determine the conflicting roles of these two molecules in the disease, we generated miR-155 (-/-) Pdcd1 (-/-) double knockout (DKO) mice. We found that ablation of programmed cell death protein 1 (PD-1) expression in miR-155-deficient mice restored the susceptibility to EAE. The increased severity of the disease in DKO mice was accompanied by an enhanced T-cell infiltration into the brain as well as an increased production of pro-inflammatory cytokines IFN-γ and IL-17. Furthermore, the major contribution of the DKO to EAE was T-cell intrinsic since adoptive transfer of CD4(+) T cells from DKO donors promoted the disease in lymphopenic recipients. These results define PD-1 deficiency in miR-155 (-/-) mice as a promoting factor of autoimmune inflammation by increasing antigen-driven T-cell expansion and infiltration.
Insights
Mice lacking both miR-155 and programmed cell death protein 1 (PD-1) show increased susceptibility to experimental autoimmune encephalomyelitis (EAE). This highlights PD-1
Area of Science:
- Immunology
- Neuroimmunology
- Autoimmune Diseases
Background:
- MicroRNA-155 (miR-155) deficiency confers resistance to experimental autoimmune encephalomyelitis (EAE).
- Programmed cell death protein 1 (PD-1) deficiency exacerbates EAE severity.
- The distinct roles of miR-155 and PD-1 in EAE pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the combined effects of miR-155 and PD-1 deficiency on EAE.
- To elucidate the mechanisms underlying the interplay between miR-155 and PD-1 in autoimmune neuroinflammation.
Main Methods:
- Generation and characterization of miR-155 (-/-) Pdcd1 (-/-) double knockout (DKO) mice.
- Assessment of EAE susceptibility and severity in DKO mice.
- Analysis of T-cell infiltration and pro-inflammatory cytokine production in the central nervous system.
- Adoptive transfer experiments using CD4(+) T cells from DKO donors.
Main Results:
- miR-155 (-/-) Pdcd1 (-/-) DKO mice exhibited restored susceptibility to EAE.
- DKO mice showed enhanced T-cell infiltration into the brain and increased production of IFN-γ and IL-17.
- T-cell intrinsic mechanisms, specifically antigen-driven T-cell expansion and infiltration, were identified as major contributors to EAE exacerbation in DKO mice.
Conclusions:
- PD-1 deficiency in miR-155-deficient mice promotes autoimmune neuroinflammation.
- The study identifies a critical role for PD-1 in regulating T-cell responses during autoimmune encephalomyelitis.
- Targeting the miR-155/PD-1 axis may offer therapeutic strategies for EAE and related autoimmune conditions.
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