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.