Strain-level antigen variation facilitates immune evasion in Bacteroides thetaiotaomicron

The T cell receptor (TCR) repertoire of intestinal CD4+ T cells is enriched for specificity towards microbiome-encoded epitopes shared among many microbiome members, providing broad microbial reactivity from a limited pool of cells. These cells actively coordinate mutualistic host-microbiome interactions, yet many epitopes are shared between gut symbionts and closely related pathobionts and pathogens. Given the disparate impacts of these agents on host health, intestinal CD4+ T cells must maintain strain-level discriminatory power to ensure protective immunity while preventing inappropriate responses against symbionts. However, to date, the mechanisms by which this occurs have remained enigmatic. To interrogate this, we leveraged B{theta}OM mice that express a transgenic TCR specific for a BT4295-encoded epitope in B. thetaiotaomicron. While many B. thetaiotaomicron strains potently activated B{theta}OM CD4+ T cells in vitro, strain dnLKV9 escaped recognition. Bioinformatic analyses uncovered two BT4295 homologs in B. thetaiotaomicron-dnLKV9, with each homolog harboring sequence modifications relative to strain VPI-5482, specifically a premature stop codon and a T548S substitution within the epitope. Reconstruction of these variants in B. thetaiotaomicron-VPI-5482{Delta}BT4295 conferred evasion from B{theta}OM CD4+ T cells in vitro to this otherwise permissive strain. Adoptive transfer of B{theta}OM CD4+ T cells to gnotobiotic RAG1-/- colonized with B. thetaiotaomicron harboring these variant BT4295 forms verified the sufficiency of these antigen modifications for evasion of B{theta}OM CD4+ T cells. Collectively, these data uncover the existence of strain-level immune evasion in B. thetaiotaomicron and reveal a mechanism whereby strains evade recognition by CD4+ T cells, facilitating strain-level discrimination in responsiveness to the microbiome.