Abstract
Due to the plasticity of IL-17-producing CD4 T cells (Th17 cells), a long-standing challenge in studying Th17-driven autoimmune is the lack of specific surface marker to identify the pathogenic Th17 cells in vivo. Recently, we discovered that pathogenic CD4 T cells were CXCR6 positive in experimental autoimmune encephalomyelitis (EAE), a commonly used Th17-driven autoimmune model. Herein, we further revealed that peripheral CXCR6+CD4 T cells contain a functionally distinct subpopulation, which is CCR6 positive and enriched for conventional Th17 molecules (IL-23R and RORγt) and cytotoxic signatures. Additionally, spinal cord-infiltrating CD4 T cells were highly cytotoxic by expressing Granzyme(s) along with IFNγ and GM-CSF. Collectively, this study suggested that peripheral CCR6+CXCR6+CD4 T cells were Th17 cells with cytotoxic property in EAE model, and highlighted the cytotoxic granzymes for EAE pathology.
Highlights
Multiple sclerosis (MS) is a devastating autoimmune disease with progressive neurological dysfunction due to demyelination of the central nerve system (CNS) [1]
CXCR6+CD4 cells dramatically accumulated in the peripheral blood of EAE mice, Cxcr6-ko and wt mice developed comparable EAE symptom [17], suggesting that CXCR6 might only serve as a marker and be dispensable for CD4 cell chemotaxis in EAE
Since CCR6 has been well established as a chemokine receptor preferentially expressed on conventional Th17 cells [18], especially the one generated in vitro, we costained the CCR6 and CXCR6 on draining lymph nodederived CD4 cells at EAE onset
Summary
Multiple sclerosis (MS) is a devastating autoimmune disease with progressive neurological dysfunction due to demyelination of the central nerve system (CNS) [1]. Th17 cells themselves are not pathogenic [4], but are converted, under the priming of myeloid cell-derived IL-1 and IL-23 [5,6,7], into pathogenic CD4 cells, which lose IL-17producing ability and alternatively produce IFNg and GM-CSF [8,9,10,11,12]. Despite their cytokine profiles, little else is known about the pathogenic CD4 cells, mainly due to the lack of specific marker to precisely identify them in vivo. Depleting CXCR6+CD4 cells by anti-CXCR6 antibody dramatically ameliorated established EAE, confirming the
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