CD28/CTLA-4/B7 costimulatory pathway blockade affects regulatory T-cell function in autoimmunity

Area of Science:

• Immunology
• Neuroimmunology
• Autoimmunity

Background:

• Naïve T cells require B7/CD28 costimulation for full activation.
• B7 blockade is explored for preventing unwanted immune reactions.
• Potential complexity arises from B7 blockade affecting regulatory T (Treg) cells and CTLA-4 signaling.

Purpose of the Study:

• To investigate the effects of B7 blockade on the autoimmune response in a mouse model of multiple sclerosis (MS).
• To determine if B7 blockade, administered during an ongoing autoimmune response, impacts disease severity and immune cell function.

Main Methods:

• Utilized the experimental autoimmune encephalomyelitis (EAE) mouse model for MS.
• Administered CTLA-4Ig (B7 blockade) at days 7 and 9 post-immunization, targeting primed myelin-reactive T cells.
• Assessed disease signs, CNS inflammation, demyelination, cytokine production (IL-17, IFN-γ), and Treg cell function (Ki67 and CTLA-4 expression).

Main Results:

• B7 blockade exacerbated EAE disease signs, leading to more severe CNS inflammation and demyelination.
• Treatment resulted in enhanced production of inflammatory cytokines IL-17 and IFN-γ.
• CTLA-4Ig treatment transiently reduced peripheral Treg cell expression of Ki67 and CTLA-4, impairing their function.

Conclusions:

• B7 blockade during a specific phase of the autoimmune response can suppress Treg cells.
• This Treg cell suppression leads to a more severe autoimmune disease, contrary to expectations for immune modulation.
• Findings highlight the complex role of B7 costimulation and Treg cells in autoimmune pathogenesis.