Toll‐like receptors control the accumulation of neutrophils in lymph nodes that expand CD4(+) T cells during experimental autoimmune encephalomyelitis

Toll‐like receptors (TLR) control the activation of dendritic cells that prime CD4(+) T cells in draining lymph nodes, where these T cells then undergo massive clonal expansion. The mechanisms controlling this clonal T cell expansion are poorly defined. Using the CD4(+) T cell‐mediated disease experimental autoimmune encephalomyelitis (EAE), we show here that this process is markedly suppressed when TLR9 signaling is increased, without noticeably affecting the transcriptome of primed T cells, indicating a purely quantitative effect on CD4(+) T cell expansion. Addressing the underpinning mechanisms revealed that CD4(+) T cell expansion was preceded and depended on the accumulation of neutrophils in lymph nodes a few days after immunization. Underlying the importance of this immune regulation pathway, blocking neutrophil accumulation in lymph nodes by treating mice with a TLR9 agonist inhibited EAE progression in mice with defects in regulatory T cells or regulatory B cells, which otherwise developed a severe chronic disease. Collectively, this study demonstrates the key role of neutrophils in the quantitative regulation of antigen‐specific CD4(+) T cell expansion in lymph nodes, and the counter‐regulatory role of TLR signaling in this process.