CD6 as a potential target for treating multiple sclerosis.

Area of Science:

• Immunology
• Neuroimmunology
• Molecular and Cellular Biology

Background:

• CD6 is a T-cell marker implicated as a risk gene for multiple sclerosis (MS).
• The exact function of CD6 in T-cell regulation and disease pathogenesis is not fully understood.
• A lack of genetically modified animal models has hindered research into CD6's role.

Purpose of the Study:

• To investigate the role of CD6 in T-cell responses and experimental autoimmune encephalomyelitis (EAE), an animal model of MS.
• To develop and evaluate a CD6-targeting therapeutic strategy for MS.

Main Methods:

• Generation and analysis of CD6 knockout (KO) mice.
• Assessment of T-cell activation, survival, proliferation, and polarization in CD6 KO mice.
• Evaluation of T-cell infiltration in the central nervous system.
• Development of CD6 humanized mice and testing of anti-human CD6 monoclonal antibodies in EAE.

Main Results:

• CD6 KO mice exhibited attenuated EAE disease severity, reduced spinal cord T-cell infiltration, and decreased pathogenic T-cell responses.
• CD6-deficient T cells showed enhanced initial activation but reduced survival and proliferation, leading to diminished Th1 and Th17 polarization.
• Activated CD6-deficient T cells displayed impaired ability to infiltrate brain microvascular endothelial cell monolayers.
• A mouse anti-human CD6 monoclonal antibody effectively treated established EAE in humanized mice without T-cell depletion.

Conclusions:

• CD6 acts as a dual regulator: a negative regulator of T-cell activation and a positive regulator of activated T-cell survival, proliferation, and infiltration.
• Targeting CD6, particularly with monoclonal antibodies, represents a promising therapeutic strategy for MS and other T-cell-mediated autoimmune diseases.