Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal...

Area of Science:

• Immunology
• Neuroscience
• Infectious Diseases

Background:

• Cryptococcal meningoencephalitis (CM) is a leading cause of neurological death, particularly in immunocompromised individuals.
• T cell-mediated inflammation is increasingly recognized as a key factor in lethal central nervous system (CNS) pathology during CM.

Purpose of the Study:

• To investigate the role of the chemokine receptor CXCR3 axis in the immunopathology of CM.
• To determine if targeting CXCR3 can mitigate CNS damage and improve outcomes in CM.

Main Methods:

• Analysis of CXCR3 expression in human patients and a murine model of CM.
• Generation and infection of CXCR3 knockout (CXCR3-/-) mice.
• Assessment of T cell infiltration, T H 1 skewing, fungal burden, neurological deficits, and neuronal damage.
• Adoptive transfer experiments using wild-type (WT) and CXCR3-/- CD4+ T cells.

Main Results:

• CXCR3 axis is significantly upregulated in human and murine CM.
• CXCR3 deletion in mice enhances survival, reduces neurological deficits, and limits neuronal damage.
• CXCR3 deficiency decreases CD4+ T cell accumulation and T H 1 skewing in the CNS, but not in the spleen.
• Adoptive transfer of WT CD4+ T cells into CXCR3-/- mice restored CM pathology, while CXCR3-/- CD4+ T cells did not.

Conclusions:

• CXCR3+ CD4+ T cells are critical drivers of lethal CNS pathology in CM.
• These T cells are not essential for fungal clearance.
• The CXCR3 pathway represents a promising therapeutic target for limiting CNS inflammatory damage in CM.