Empirical modeling of T cell activation predicts interplay of host cytokines and bacterial indole

5 years ago

Empirical modeling of T cell activation predicts interplay of host cytokines and bacterial indole

Shelby Steinmeyer, Arul Jayaraman, Juergen Hahn, Robert C. Alaniz, Daniel P. Howsmon

Adoptive transfer of anti-inflammatory FOXP3+ Tregs has gained attention as a new therapeutic strategy for auto-inflammatory disorders such as Inflammatory Bowel Disease. The isolated cells are conditioned in vitro to obtain a sufficient number of anti-inflammatory FOXP3+ Tregs that can be reintroduced into the patient to potentially reduce the pathologic inflammatory response. Previous evidence suggests that microbiota metabolites can potentially condition cells during the in vitro expansion/differentiation step. However, the number of combinations of cytokines and metabolites that can be varied is large, preventing a purely experimental investigation which would determine optimal cell therapeutic outcomes. To address this problem, a combined experimental and modeling approached is investigated here: an artificial neural network model was trained to predict the steady-state T cell population phenotype after differentiation with a variety of host cytokines and the microbial metabolite indole. This artificial neural network model was able to both reliably predict the phenotype of these T cell populations and also uncover unexpected conditions for optimal Treg differentiation that were subsequently verified experimentally. Biotechnol. Bioeng. 2017;9999: 1–8. © 2017 Wiley Periodicals, Inc. Empirical modeling of T cell differentiation predicts anti-inflammatory effects of the bacterial metabolite indole. Additionally, novel interactions of host cytokines and indole emerge, suggesting stimulation conditions that can be used to simultaneously maximize differentiation toward anti-inflammatory Tregs and minimize pro-inflammatory Th17 cells. This work highlights the utility of incorporating bacterial signals such as indole in the differentiation step prior to transplantation in T cell adoptive transfer.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/bit.26371