Computational modeling of complex bioenergetic mechanisms that modulate CD4+ T cell effector and regulatory functions.

We built a computational model of complex mechanisms at the intersection of immunity and metabolism that regulate CD4+ T cell effector and regulatory functions by using coupled ordinary differential equations. The model provides an improved understanding of how CD4+ T cells are shaping the immune response during Clostridioides difficile infection (CDI), and how they may be targeted pharmacologically to produce a more robust regulatory (Treg) response, which is associated with improved disease outcomes during CDI and other diseases. LANCL2 activation during CDI decreased the effector response, increased regulatory response, and elicited metabolic changes that favored Treg. Interestingly, LANCL2 activation provided greater immune and metabolic modulation compared to the addition of exogenous IL-2. Additionally, we identified gluconeogenesis via PEPCK-M as potentially responsible for increased immunosuppressive behavior in Treg cells. The model can perturb immune signaling and metabolism within a CD4+ T cell and obtain clinically relevant outcomes that help identify novel drug targets for infectious, autoimmune, metabolic, and neurodegenerative diseases.