Targeted suppression of autoreactive CD8⁺ T-cell activation using blocking anti-CD8 antibodies

Area of Science:

• Immunology
• Autoimmunity
• T-cell biology

Background:

• CD8+ T-cells are implicated in autoimmune diseases like multiple sclerosis and type 1 diabetes.
• Broadly targeting CD8+ T-cells risks severe side effects, including increased infection susceptibility.
• A selective approach to modulate autoreactive CD8+ T-cells is needed.

Purpose of the Study:

• To investigate the differential dependence of autoreactive versus pathogen-specific CD8+ T-cells on CD8 for T-cell receptor (TCR) mediated activation.
• To explore the potential of targeting CD8 for selective suppression of autoreactive T-cells.

Main Methods:

• Analysis of CD8 dependence for ligand-induced T-cell receptor (TCR) activation in autoreactive and pathogen-specific CD8+ T-cells.
• Investigation of the relationship between T-cell receptor (TCR) affinity for peptide-major histocompatibility complex class I (pMHCI) and CD8 dependence.
• Assessment of the efficacy of 'blocking' anti-CD8 antibodies in suppressing autoreactive CD8+ T-cell activation.

Main Results:

• Autoreactive CD8+ T-cells exhibit high dependence on CD8 for TCR-induced activation.
• Pathogen-specific CD8+ T-cells are relatively CD8-independent.
• This dichotomy in CD8 dependence correlates with differences in TCR binding affinity to cognate peptide-major histocompatibility complex class I (pMHCI).
• 'Blocking' anti-CD8 antibodies selectively suppressed autoreactive CD8+ T-cell activation.

Conclusions:

• A fundamental difference exists in CD8 dependence between autoreactive and pathogen-specific CD8+ T-cells, linked to TCR affinity.
• Targeting CD8 offers a selective strategy to inhibit autoreactive T-cells while sparing protective immune responses.
• These findings support the development of novel therapeutics for autoimmune diseases targeting the CD8+ T-cell compartment.