Th103 - TCF1 Expression Defines Functional Th2 Heterogeneity in Tissues with Type 2 Inflammation

Abstract Text: Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, ongoing antigen exposure in allergic disease results in aberrant, sustained T cell responses. We recently defined a novel human Th2 cell state, the Th2 multipotent progenitor, through single cell RNA sequencing (scRNAseq), single cell TCR sequencing, and ex vivo function studies. These cells co-express TCF1 and LEF1, transcription factors critical for chronic and memory T cell responses, and differentiate into effector cells while maintaining self-renewal capacity. We propose that this chronically activated tissue memory population may sustain chronic inflammation in type 2 disease. To understand the factors that modulate Th2 progenitors, we established a mouse model of chronic pulmonary type 2 inflammation. We found that type 2 inflammation was broadly sustained over months despite chronic stimulation. Th2 cells in the lung parenchyma during chronic inflammation were heterogeneous and included a TCF1(+)ST2(-) compartment reminiscent of the human Th2-MPP population. These cells could self-renew for weeks without contribution from the draining lymph node. scRNAseq analysis of acute and chronic responses defined divergent effector programs, as well as the transcriptional signature of tissue Th2 progenitors. After adoptive transfer, parenchymal Th2 progenitors could self-renew and differentiate into TCF1(+)ST2(+) and TCF1(-)ST2(+) effector cells. Moreover, Th2 progenitors, but not Th2 effectors or ILC2s, were sufficient to initiate and sustain allergic inflammation over time. Our findings define the function of progenitor Th2 cells with the capacity to sustain chronic type 2 inflammation in the face of ongoing antigen exposure