Gene expression profile of all CD4 T cells from the mesenteric lymph nodes of SPF and Nippostrongylus Brasiliensis infected mice

The discovery of naïve T cell transcriptional heterogeneity in specific-pathogen-free (SPF) mice represents a paradigm shift. While the ablation of Vista can alter the proportion of naïve CD4+ T cells with unique transcriptional signatures and the ‘readiness’ of the mice to break tolerance, the effect of non-heritable environmental exposures to commensals or infections remains entirely unknown. This is especially significant since individual variance in immune response, rather than being genetically inherited, is mostly attributed to environmental factors. Here we demonstrate that transcriptional heterogeneity characterizes even the germ-free (GF) mouse naïve CD4+ T cells. Naïve CD4+ T cell transcriptional subsets and their proportions were identical between GF, SPF and conventionalized GF mice, thus commensal-independent. Notwithstanding, Nippostrongylus brasiliensis (N.b.) infection altered the proportions of these transcriptional subsets, and the appearance of cells with a unique transcriptional signature. These naïve T cell-intrinsic changes accounted for the decreased immunization response of mice to an unrelated antigen. The compositional and functional changes in the naïve CD4+ T cell pool were dependent-variables of helminth infection, regressing with N.b. clearance. Therefore, naïve T cells are not uniformly uncommitted substrates for antigen-dependent activation but actively integrate environmental cues to permute the magnitude of the immune response.