Transcription factor TCF-1 regulates the functions but not the development of lymphoid tissue inducer subsets in different tissues [single-cell RNA-seq]

Lymphoid tissue inducer (LTi) cells, known to be critical for the generation of secondary lymphoid tissues, are the founding member of innate lymphoid cells (ILCs). However, how the development and functions of this ILC subset are regulated is far from clear. In this study, we discovered a striking role of the transcription factor TCF-1 in the development of Peyer's patches (PPs) but not lymph nodes (LNs). Despite TCF-1 is critical for ILC development at multiple stages, we found normal development of LTi cells in TCF-1-deficient mice indicating that dysfunction of these LTi cells led to the deficiency in Peyer's patches formation. Through bulk and single cell RNA-Seq, we found differential gene expression patterns between LTi cells from the PPs, LNs and the small intestine laminal propria (siLP), and an important role of TCF-1 in regulating the expression of lymphotoxin (LT) specifically in PP LTi cells. Mechanistically, TCF-1 may regulate Lta indirectly through promoting the expression of GATA3, a critical transcription factor in regulating LTi functions. LTßR agonist injection during the embryonic stage partially rescued the formation of PPs in the TCF-1-deficient mice. Thus, a dose effect of LT expression in LTi cells regulated by TCF-1 contributes to a differential regulation of organogenesis of distinct secondary lymphoid structures. Overall design: ILC inducers from bone marrow of WT and Tcf7flox;Vav-Cre mice were collected for Single-cell RNA-Seq.