TNFR2 on non‐haematopoietic cells is required for Foxp3⁺ Treg‐cell function and disease suppression in EAE

Abstract

The TNF/TNFR system exerts multiple proinflammatory and immunosuppressive functions in the pathogenesis of chronic inflammation and autoimmunity. In EAE, the experimental model of Multiple Sclerosis (MS), genetic ablation of TNFR2, results in exacerbated immune reactivity and chronic disease course. The underlying mechanism driving this immunosuppressive function of TNFR2 remains unclear. We show here that chronic exacerbated EAE in TNFR2 KO mice is associated with increased Th17-cell responses and reduced numbers of Foxp3 1 Treg cells both in the spinal cord and peripheral lymphoid organs. Treg cells from TNFR2-deficient animals developing EAE show decreased proliferative and suppressive functions, both ex vivo and in vivo, and appear responsible for the exacerbated non-remitting disease, as evidenced by phenotypic rescue following adoptive transfer of Treg cells from WT but not TNFR2 À/À donors. Reciprocal BM transplantation experiments between WT and TNFR2-deficient mice demonstrated that the capacity of TNFR2 to support Treg-cell expansion and function during EAE is non-intrinsic to Treg or other haematopoietic cells but requires expression of TNFR2 in radiation-resistant cells of the host. These results reveal a previously unsuspected role for non-haematopoietic TNFR2 in modulating Treg-cell expansion and immune suppression during development of autoimmunity and suggest that a similar mechanism may affect chronicity and relapses characterizing human autoimmune disease, including MS.Key words: Animal models . Autoimmunity . Cellular immunology . Multiple sclerosis . TNFRZ Supporting Information available online IntroductionMultiple sclerosis (MS) is a chronic neuroimmunological disease characterized by disseminated foci of inflammatory demyelination in the brain and spinal cord (SC), commonly affecting young adults between the age of 20 and 40. Typically, MS has a relapsing and remitting course followed by the development of irreversible neurological disability due to persistent axonal dysfunction and neuronal loss. CNS demyelination, the pathological hallmark of MS is brought about by autoreactive à These authors contributed equally to this work. , which produces T-cell-driven demyelination with components from cellular and humoral immunity leading to axonal injury associated with disability ranging from mild weakness to severe paralysis [3,4]. Dysfunctional immune suppressive/tolerogenic mechanisms causing aggressive autoimmune behavior and demyelination are thought to play a dominant pathogenic role both in EAE and MS [1,3]. Chronicity and relapses in autoimmune diseases including MS seem to involve defective integration of inflammatory and antiinflammatory cues. Numerous studies have dissected the multiple and opposing roles of cytokine-producing cells in the autoimmune pathogenesis of MS and EAE. IL-17-(Th17) [5,6] and IFN-g-(Th1) [7][8][9][10] producing cells are considered the effector T (Teff) cells that have been detected in SC lesions at different stages of the disease progression and are thought t...

Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis

“…These data suggest that astrocytic FasL expression predominantly contributes to elimination of activated disease-promoting CD25 + CD4 + T cells but not of protective regulatory Foxp3 + CD4 + T cells in order to recover from EAE and to achieve a restitutio ad integrum. These data are in line with previous reports illustrating that astrocytes induce a regulatory phenotype in autoimmune CD4 + T cells [25], which play an important protective role in EAE [26,27]. In agreement, the number of GM-CSF-producing CD4 + T cells, i.e.…”

“…indicating that homing of myelin-specific leucocytes was not regulated by astrocytic FasL expression. In addition, the clinical score of GFAP-Cre regulatory phenotype in autoimmune CD4 + T cells [25], which play an important protective role in EAE [26,27]. In agreement, the number of GM-CSF-producing CD4 + T cells, i.e.…”

Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases

“…In SLE (and multiple sclerosis), TNF inhibitors have not performed well 217,218 , and in some cases promote lupus-like disease 219 . Although the reason for this outcome is unclear, studies suggest that inhibition of TNF binding to TNFR2 can impair the expansion of suppressive CD4 + Foxp3 + T reg cells, which maintain immune tolerance in some settings 220–222 . In this regard, similar functional observations have also been drawn for OX40, 4-1BB, CD27, DR3 and GITR.…”

T cell subsets and their signature cytokines in autoimmune and inflammatory diseases

“…It also remains an enigma as to how regulatory Th cells abolish Foxp3 expression and convert into pathogenic IFN-γ producing Th1-like cells in the presence of high levels of IFN-γ 45,46 , and why Th17 cells are differentiating into IFN-γ producing cells which are highly encephalitogenic in EAE 47 . The pleiotropic effects of Th1 cells in autoimmune disease pathology are associated not only with IFN-γ, but also with TNF, which was shown to be an important mediator in the induction of EAE 41 , but it can also mediate CNS remyelination 48 and modulate the function of Tregs, both in EAE 49 and SLE 50 .…”