Swift Entry of Myelin-Specific T Lymphocytes into the Central Nervous System in Spontaneous Autoimmune Encephalomyelitis

Abstract

Strong evidence supports that CNS-specific CD4+ T cells are central to the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Using a model of spontaneous EAE, we demonstrated that myelin basic protein (MBP)-specific CD4+ T cells up-regulate activation markers in the CNS-draining cervical lymph nodes at a time when there is no T cell activation anywhere else, including the CNS, and before the appearance of clinical signs. In spontaneous EAE, the number of MBP-specific T cell numbers does not build up gradually in the CNS; instead, a swift migration of IFN-γ-producing T cells into the CNS takes place ~24 h before the onset of neurological signs of EAE. Surgical excision of the cervical lymph nodes in healthy pre-EAE transgenic mice delayed the onset of EAE and resulted in a less severe disease. In EAE induced by immunization with MBP/CFA, a similar activation of T cells in the draining lymph nodes of the injection site precedes the disease. Taken together, our results suggest that peripheral activation of T cells in draining lymph nodes is an early event in the development of EAE, which paves the way for the initial burst of IFN-γ-producing CD4+ T cell into the CNS.

T Cell Apoptosis and Induction of Foxp3+ Regulatory T Cells Underlie the Therapeutic Efficacy of CD4 Blockade in Experimental Autoimmune Encephalomyelitis

“…It is well described that in EAE, the CNS suffers a massive infiltration by activated lymphocytes, namely CD4 effector T cells, which break the blood-brain barrier and recruit other proinflammatory cells to the site of inflammation, leading to an increased severity of the disease (64). We found that anti-CD4-treated mice did not show any significant infiltrates in the CNS while presenting a reduction of MOG-specific TCR-transgenic cells in the cervical lymph node (the number of nontransgenic CD4 cells did not change, confirming the nondepleting nature of the mAb used).…”

Ocular Surface APCs Are Necessary for Autoreactive T Cell-Mediated Experimental Autoimmune Lacrimal Keratoconjunctivitis

“…The current findings are also consistent with similar studies using other inflammatory models with a high degree of peripheral lymphatic drainage to the CLNs. For example, surgical excision of the CLNs delayed the onset and reduced clinical disease in the neuroinflammatory model of experimental autoimmune encephalomyelitis (35,36), and cervical lymphadenectomy dramatically reversed corneal allograft rejection to a survival rate of 92% compared with 0% survival noted in the eyes of mice with intact CLNs (37).…”

Loss of Allograft Inflammatory Factor-1 Ameliorates Experimental Autoimmune Encephalomyelitis by Limiting Encephalitogenic CD4 T-Cell Expansion

“…In EAE, myelin-specific T cells are activated in the periphery and migrate into the CNS by crossing the blood-brain barrier (30,31). To investigate if the decreases in disease activity and CNS infiltration and preserved myelin observed in Aif-1-deficient mice (Figures 1-3 Figure S2B), FACS analysis failed to find significant genotype-dependent differences in T-cell subsets.…”