CCR5 ameliorates Japanese encephalitis via dictating the equilibrium of regulatory CD4(+)Foxp3(+) T and IL-17(+)CD4(+) Th17 cells.

Abstract

BACKGROUND:

CCR5 is a CC chemokine receptor involved in the migration of effector leukocytes including macrophages, NK, and T cells into inflamed tissues. Also, the role of CCR5 in CD4(+)Foxp3(+) regulatory T cell (Treg) homing has recently begun to grab attention. Japanese encephalitis (JE) is defined as severe neuroinflammation of the central nervous system (CNS) following infection with mosquito-borne flavivirus JE virus. However, the potential contribution of CCR5 to JE progression via mediating CD4(+)Foxp3(+) Treg homing has not been investigated.

METHODS:

Infected wild-type (Ccr5(+/+)) and CCR5-deficient (Ccr5(-/-)) mice were examined daily for mortality and clinical signs, and neuroinflammation in the CNS was evaluated by infiltration of inflammatory leukocytes and cytokine expression. In addition, viral burden, NK- and JEV-specific T cell responses were analyzed. Adoptive transfer of CCR5(+)CD4(+)Foxp3(+) Tregs was used to evaluate the role of Tregs in JE progression.

RESULTS:

CCR5 ablation exacerbated JE without altering viral burden in the extraneural and CNS tissues, as manifested by increased CNS infiltration of Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. Compared to Ccr5(+/+) mice, Ccr5(-/-) mice unexpectedly showed increased responses of IFN-γ(+)NK and CD8(+) T cells in the spleen, but not CD4(+) T cells. More interestingly, CCR5-ablation resulted in a skewed response to IL-17(+)CD4(+) Th17 cells and correspondingly reduced CD4(+)Foxp3(+) Tregs in the spleen and brain, which was closely associated with exacerbated JE. Our results also revealed that adoptive transfer of sorted CCR5(+)CD4(+)Foxp3(+) Tregs into Ccr5(-/-) mice could ameliorate JE progression without apparently altering the viral burden and CNS infiltration of IL-17(+)CD4(+) Th17 cells, myeloid-derived Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. Instead, adoptive transfer of CCR5(+)CD4(+)Foxp3(+) Tregs into Ccr5(-/-) mice resulted in increased expression of anti-inflammatory cytokines (IL-10 and TGF-β) in the spleen and brain, and transferred CCR5(+) Tregs were found to produce IL-10.

CONCLUSIONS:

CCR5 regulates JE progression via governing timely and appropriate CNS infiltration of CD4(+)Foxp3(+) Tregs, thereby facilitating host survival. Therefore, this critical and extended role of CCR5 in JE raises possible safety concerns regarding the use of CCR5 antagonists in human immunodeficiency virus (HIV)-infected individuals who inhabit regions in which both HIV and flaviviruses, such as JEV and West Nile virus, are endemic.

• Authors: Jin Hyoung Kim, Ajit Mahadev Patil, Jin Young Choi, Seong Bum Kim, Erdenebelig Uyangaa, Ferdaus Mohd Altaf Hossain, Sang-Youel Park, John Hwa Lee, Seong Kug Eo
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 13 Issue 1 Pg. 223 (07 20 2016) ISSN: 1742-2094 [Electronic] England
• PMID: 27439902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCR5 protein, mouse
• Cytokines
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-17
• Receptors, CCR5

Topics

• Animals
• CD4-Positive T-Lymphocytes (metabolism)
• Cell Movement (physiology)
• Central Nervous System (metabolism, pathology, virology)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Disease Progression
• Encephalitis, Japanese (genetics, pathology)
• Female
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation (physiology)
• Interleukin-17 (genetics, metabolism)
• Killer Cells, Natural (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myeloid Cells (metabolism, pathology, virology)
• Receptors, CCR5 (genetics, metabolism)
• Spleen (metabolism, pathology, virology)
• Th17 Cells (metabolism)
• Virus Replication (genetics)