Heterogeneity and plasticity of the naïve CD4⁺ T cell compartment

While naïve CD4⁺ T cells have historically been considered a homogenous population, recent studies have provided evidence that functional heterogeneity exists within this population. Using single cell RNA sequencing (scRNAseq), we identify five transcriptionally distinct naïve CD4⁺ T cell subsets that emerge within the single positive stage in the thymus: a quiescence cluster (T^Q), a memory-like cluster (T^MEM), a TCR reactive cluster (T^TCR), an IFN responsive cluster (T^IFN), and an undifferentiated cluster (T^UND). Elevated expression of transcription factors KLF2, Mx1, and Nur77 within the T^Q, T^IFN, and T^MEM clusters, respectively, allowed enrichment of these subsets for further analyses. Functional studies using sorted cells revealed that naïve T cell subsets have distinctive functional biases upon stimulation. Furthermore, treatment of mice with inflammatory stimuli imparted a state of reduced responsiveness on naïve T cells, evidenced by a reduction in cytokine production ex vivo. In human lupus patients, naïve CD4⁺ T cell cluster frequencies were distorted, with the T^IFN cluster expanding proportionately with disease score. Our data show that naïve T cells are influenced by host environment, with functional consequences manifesting upon activation. These findings highlight a need to explore how naïve T cells can become distorted in cancer, autoimmunity, and infectious diseases.