Evolution of molecular pathways of Tregs mediated Suppression

Abstract Treg suppression of conventional T cells is a fundamental step in regulating the adaptive immune system function. It is known that Treg first appeared in vertebrates. However little is known about the evolutionary history of suppression pathways mediated by Tregs. We employed AI text mining system to highlight the suppression pathways currently known to be utilized by Tregs. Our system identified various pathways such as CTLA4, induction of apoptosis, calcium signaling, inhibition of NfkB and NFAT. After that we employed phylogenetic analysis including multiple sequence alignment, phylogenetic tree building, ancestral sequence reconstruction, neutrality tests and positive selection test to investigate the evolutionary history of Treg mediated pathways in more details. We found that CTLA4 first appeared in vertebrates possibly rising from an IGV containing protein in cartilaginous fish. Conversely, we found that Tregs repurposed ancient pathways such as Calcineurin and CAMP Response Element Modulator that both exists as far as amoeba. Interestingly we found that these two pathways were highly conserved between vertebrates and lower invertebrates indicating conservation of function. Taken together, our research indicate that Tregs evolved its regulatory systems that evolved in vertebrates as well as reused conserved ancient regulatory systems that are related to the innate immune system.