New molecule, BHLHe40, links adjuvant activity of pertussis toxin to T cell pathogenicity in brain inflammation

Multiple sclerosis (MS) is a human neuro-inflammatory disease of autoimmune nature. Mouse model of MS is called experimental autoimmune encephalomyelitis (EAE) and it's induction in mice depends on dirty little secret: to induce EAE, mice are injected not just with peptide derived from myelin oligodendrocyte glycoprotein (MOG35-55) emulsified in CFA (to activate T cells) but mice are also injected with the co-adjuvant pertussis toxin (PTX), an ADP-ribosylating exotoxin derived from Bordetella pertussis (PTX is a whooping cough toxin that has been shown to be necessary for MS induction in this mouse model). No one really knows how or what way PTX primes mice for MS/EAE induction or why we even needed it in the first place (by the way, next time you hear that another drug failed in clinical trial for multiple sclerosis you know now it is because mouse model is completely artificial).

In this regard, new paper in Journal of Experinental Medicine is of interest. The authors report that transcription factor basic helix–loop–helix family member e40 (BHLHe40) was required for adjuvant activity of PTX for EAE development.

Using BHLHe40^GFP mice the authors first showed that CD4 T cells expressing GFP (surrogate marker for BHLHe40) were enriched for effector T cells expressing cytokines implicated in EAE pathology (IFN-γ, IL-17, GM-CSF).

Next, the authors showed that ADP-ribosylating activity of PTX was necessary to augment GFP/BHLHe40 expression in T cells and to induce EAE.

Adoptive transfer of BHLHe40-deficient 2D2 T cells (that are specific for MOG peptide) confirmed that BHLHe40 expression was required for T cell pathogenicity in EAE.

In summary, this study showed that during EAE induction PTX sensitizes both innate cells (for IL-1 production) and adaptive immune T cells (for GM-CSF and IFN-γ production) via action of BHLHe40.

David Usharauli