A Role for Macrophage Inflammatory Protein-3α/CC Chemokine Ligand 20 in Immune Priming During T Cell-Mediated Inflammation of the Central Nervous System

Abstract

Chemokines are a family of cytokines that exhibit selective chemoattractant properties for target leukocytes and play a significant role in leukocyte migration. In this study, we have investigated the role of the C-C chemokine, macrophage inflammatory protein (MIP)-3α/CC chemokine ligand 20, in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of T cell-dependent inflammation. Expression in the CNS of MIP-3α, as determined by RT-PCR, increased in a time-dependent manner such that peak expression correlated with peak clinical disease. Similarly, levels of immunoreactive MIP-3α in the draining lymph nodes increased up to 10-fold 9 days postimmunization and remained elevated for up to 21 days postimmunization. The increased production of MIP-3α coincided with onset of clinical disease. Treatment of mice with specific neutralizing anti-MIP-3α Abs significantly reduced the severity of both clinical EAE and neuroinflammation by inhibiting the sensitization of lymphocytes to the specific Ag and release of lymphocytes from the draining lymph nodes. In contrast, adoptive transfer experiments indicated that MIP-3α was not essential for the effector phase of EAE. Together, these data demonstrate that MIP-3α plays a critical role in the sensitization phase of EAE.

CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T‐cell recruitment to target tissues

“…Furthermore, final CS for EAE-associated symptoms were higher in CCR6 À/À mice, indicating that once clinical disease appears, CCR6 is not essential during the effector phase. Our hypothesis concurs with reports that CCL20 neutralization does not prevent passive transfer of EAE using encephalitogenic T cells [14], indicating that the CCR6/CCL20 pair is not necessary for the disease effector phase. We show that Th17 cells development in vivo is unaffected by CCR6 deficiency, either in naive mice [27] or in response to antigen; percentages of IL-17-expressing CD4 1 T cells in DLN were similar in MOG-immunized CCR6 À/À and WT mice.…”

“…Furthermore, final CS for EAE-associated symptoms were higher in CCR6 À/À mice, indicating that once clinical disease appears, CCR6 is not essential during the effector phase. Our hypothesis concurs with reports that CCL20 neutralization does not prevent passive transfer of EAE using encephalitogenic T cells [14], indicating that the CCR6/CCL20 pair is not necessary for the disease effector phase.…”

“…Reduced disease severity following administration of neutralizing anti-CCL20 mAb at the time of EAE induction led Kohler et al to suggest a role for CCL20 also in the sensitization phase [14]. Whether or not the CCR6/CCL20 pair facilitates antigen presentation during preclinical disease, our results show that CCR6 deficiency does not alter the development or function of MOG-primed cells in lymphoid organs.…”

“…CCL20 expression is upregulated in both the CNS and the draining LN (DLN) during clinical disease; the major intracerebral source of CCL20 is infiltrating lymphocytes at disease onset and astrocytes during relapse [13,14]. Administration of neutralizing anti-CCL20 Ab at the time of EAE induction reduces disease severity, suggesting a role for this chemokine in the sensitization phase of EAE, although adoptive transfer experiments with reactive T cells indicate that CCL20 is not necessary for the effector phase of disease [14]. After disease induction in mice, CCR6 1 Treg are enriched in peripheral blood and accumulate in the CNS [15].…”

Control of Salmonella dissemination in vivo by macrophage inflammatory protein (MIP)-3α/CCL20

“…[19][20][21] S. enteritidis strain 11RX and Staphylococcus aureus 22 were obtained from stocks within the School of Molecular and Biomedical Science at the University of Adelaide. Zymosan was obtained from the Sigma Chemical Co. (St Louis, MO, USA).…”