Environmental conditioning by type I interferons poises naive CD4+ T cells for transition to precursor central memory cells

Upon antigenic stimulation, naïve CD4+ T cells differentiate into phenotypically distinct T helper cells. Naïve T cells are considered homogenous save for their unique T cell receptor (TCR), thought to confer distinct differentiation potential according to its affinity for cognate antigen. Here we show that naïve T cells are transcriptionally heterogeneous and identify a role for type I interferon (IFN) in shaping this heterogeneity. Using complementary single cell analyses, we show that T cell fate is independent of TCR and identify a role for type I IFN signaling in regulating the early differentiation of naïve CD4 T cells towards central memory precursors. Thus, naïve CD4 T cell differentiation potential is determined by environmental cues both prior to and during priming. IFN-conditioned naïve CD4 T cells are expanded in human viral infection and autoimmunity highlighting the relevance of this pathway to beneficial and maladaptive T cell responses, as well as its therapeutic potential for enhanced T cell memory formation. Single-cell RNA sequencing was performed on mouse splenic CD4 T cells. Naïve CD4 T cells from transgenic TCR (tgTCR) Smarta and C7 mice (two replicates each) were adoptively transferred into congenic recipients and profiled at steady state along with host naïve CD4 T cells. To study in vivo C7 differentiation, adoptively transferred tgTCR C7 T cells were profiled 16hr (two replicates) and 40hr post L. monocytogenes-ESAT infection. Additionally, gp66:I-Ab tetramer+ T cells were sorted from an Lm-gp66 infected mouse 7 days post intravenous infection (two replicates) and profiled with single-cell 5' RNA-seq + TCR-seq.