Treg cells mediate recovery from EAE by controlling effector T cell proliferation and motility in the CNS

Regulatory T cells are crucial in controlling various functions of effector T cells during experimental autoimmune encephalomyelitis. While regulatory T cells are reported to exert their immunomodulatory effects in the peripheral immune organs, their role within the central nervous system (CNS) during experimental autoimmune encephalomyelitis is unclear. Here, by combining a selectively timed regulatory T cells depletion with 2-photon microscopy, we report that regulatory T cells exercise their dynamic control over effector T cells in the CNS. Acute depletion of regulatory T cells exacerbated experimental aut oimmune encephalomyelitis sev erity which was accompanied by increased pro-inflammatory cytokine production and prolifer ation of effector T cells. Intravital microscopy revealed that, in the absence of regulatory T cells, the velocity of effector T cells was decreased with simultaneous increase in the proportion of stationary phase cells in the CNS. Based on these data, we conclude that regulatory T cells mediate recovery from experimental autoimmune encephalomyelitis by controlling cytokine production, proliferation and motility of effector T cells in the CNS

Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination

Active multiple sclerosis lesions show inflammatory changes suggestive of a combined attack by autoreactive T and B lymphocytes against brain white matter. These pathogenic immune cells derive from progenitors that are normal, innocuous components of the healthy immune repertoire but become autoaggressive upon pathological activation. The stimuli triggering this autoimmune conversion have been commonly attributed to environmental factors, in particular microbial infection. However, using the relapsing-remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis, here we show that the commensal gut flora-in the absence of pathogenic agents-is essential in triggering immune processes, leading to a relapsing-remitting autoimmune disease driven by myelin-specific CD4(+) T cells. We show further that recruitment and activation of autoantibody-producing B cells from the endogenous immune repertoire depends on availability of the target autoantigen, myelin oligodendrocyte glycoprotein (MOG), and commensal microbiota. Our observations identify a sequence of events triggering organ-specific autoimmune disease and these processes may offer novel therapeutic targets

Myeloid-derived suppressor cells control B cell accumulation in the central nervous system during autoimmunity

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) have been characterized in the context of malignancies. Here we show that PMN-MDSCs can restrain B cell accumulation during central nervous system (CNS) autoimmunity. Ly6G+ cells were recruited to the CNS during experimental autoimmune encephalomyelitis (EAE), interacted with B cells that produced the cytokines GM-CSF and interleukin-6 (IL-6), and acquired properties of PMN-MDSCs in the CNS in a manner dependent on the signal transducer STAT3. Depletion of Ly6G+ cells or dysfunction of Ly6G+ cells through conditional ablation of STAT3 led to the selective accumulation of GM-CSF-producing B cells in the CNS compartment, which in turn promoted an activated microglial phenotype and lack of recovery from EAE. The frequency of CD138+ B cells in the cerebrospinal fluid (CSF) of human subjects with multiple sclerosis was negatively correlated with the frequency of PMN-MDSCs in the CSF. Thus PMN-MDSCs might selectively control the accumulation and cytokine secretion of B cells in the inflamed CNS