Heterogeneity and plasticity of the naive CD4+ T cell compartment [Bulk RNAseq]

While naive CD4+ T cells have historically been considered a homogenous population, recent studies provide evidence that functional heterogeneity exists. Using scRNAseq, we identified five transcriptionally distinct naive CD4+ T cell subsets that emerge within the single positive stage in the thymus: a quiescence cluster (TQ), a memory-like cluster (TMEM), a TCR-reactive cluster (TTCR), an IFN-responsive cluster (TIFN), and an undifferentiated cluster (TUND). Elevated expression of transcription factors KLF2, Mx1, and Nur77 within the TQ, TIFN, and TTCR clusters, respectively, enabled enrichment of these subsets for functional validation. Sorted subsets displayed distinctive functional responses upon stimulation. Furthermore, treatment of mice with inflammatory stimuli reduced cytokine production of naive T cells ex vivo. In SLE patients, IFN-induced gene expression was markedly elevated within the TIFN cluster. Our data demonstrate that naive T cells are shaped by their host environment, with functional biases manifesting upon activation. These findings highlight the importance of understanding how naive T cell heterogeneity may be distorted in cancer, autoimmunity, and infectious diseases.