T cell recognition is shaped by epitope sequence conservation in the host proteome and microbiome (LYM7P.612)

Abstract Several mechanisms exist to avoid or suppress inflammatory T cell immune responses that could prove harmful to the host by targeting self-antigens or commensal microbes. We hypothesized that these mechanisms could be evident when comparing the immunogenicity of a peptide with the conservation of its sequence in the human proteome or the healthy human microbiome. We utilized the Immune Epitope Database (IEDB) to retrieve experimentally characterized T cell epitopes derived from bacteria that are targets of inflammatory human immune responses. Indeed, we found that epitopes that are homologous with self-antigens above a certain threshold showed lower immunogenicity, presumably as a result of negative selection of T cells capable of recognizing such peptides. Moreover, we also found a reduced level of immune recognition for epitopes conserved in the commensal microbiome, presumably as a result of peripheral tolerance. Interestingly, we found evidence that the microbiota of different body sites play different roles in the tolerization of T cells. For example, peptides conserved among bacteria of the gastrointestinal tract had lower immunogenicity than those conserved in bacteria of the lung microbiome. Overall, these findings indicate that the existence (and potentially the polarization) of T cell responses to a given epitope is influenced and to some extend predictable based on its homology to antigens shaping the immune response.