Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis

Area of Science:

• Neuroimmunology
• Immunology
• Pathogenesis of Multiple Sclerosis

Background:

• Inflammatory foci localization in the cerebellum correlates with severe outcomes in multiple sclerosis (MS).
• Experimental autoimmune encephalomyelitis (EAE) models show distinct clinical outcomes linked to IFN-gamma production and inflammatory cell localization.
• IFN-gamma deficient mice develop EAE with inflammation localized to the cerebellum and brain stem, unlike wild-type mice with spinal cord inflammation.

Purpose of the Study:

• To investigate the role of host central nervous system (CNS) sensing of T cell-produced IFN-gamma in determining neuroinflammation sites during EAE.
• To elucidate how IFN-gamma interaction with CNS cells during EAE initiation influences neuroinflammation and pathogenesis.

Main Methods:

• Utilized an adoptive transfer system in EAE models.
• Transferred wild-type (WT) Th1 cells into IFN-gamma receptor-deficient mice.
• Transferred IFN-gamma-deficient T cells to WT hosts.
• Cotransferred CNS antigen-specific WT Th1 cells with IFN-gamma-deficient T cells.

Main Results:

• Transfer of WT Th1 cells into IFN-gamma receptor-deficient mice led to pathogenic invasion of the brain stem and cerebellum, mimicking disease in WT hosts receiving IFN-gamma-deficient T cells.
• Spinal cord inflammation typical of EAE was abrogated in both IFN-gamma-deficient systems.
• Cotransferring WT Th1 cells with IFN-gamma-deficient T cells restored spinal cord invasion while blocking cerebellar and brain stem invasion.

Conclusions:

• The CNS's ability to sense pathogenic T cell-derived IFN-gamma during EAE initiation is critical in determining the sites of CNS pathogenesis.
• IFN-gamma signaling during EAE initiation can selectively promote or suppress neuroinflammation and disease progression.
• This interaction highlights a mechanism for selective control of neuroinflammation in MS pathogenesis.