Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling molecules

Abstract

Hepatocyte nuclear factor 4 α (HNF4A) is a highly conserved nuclear receptor that has been associated with ulcerative colitis. In mice, HNF4A is indispensable for the maintenance of intestinal homeostasis, yet the underlying mechanisms are poorly characterized. Here, we demonstrate that the expression of HNF4A in intestinal epithelial cells (IECs) is required for the proper development and composition of the intraepithelial lymphocyte (IEL) compartment. HNF4A directly regulates expression of immune signaling molecules including butyrophilin-like (Btnl) 1, Btnl6, H2-T3, and Clec2e that control IEC–IEL crosstalk. HNF4A selectively enhances the expansion of natural IELs that are TCRγδ+ or TCRαβ+CD8αα+ to shape the composition of IEL compartment. In the small intestine, HNF4A cooperates with its paralog HNF4G, to drive expression of immune signaling molecules. Moreover, the HNF4A–BTNL regulatory axis is conserved in human IECs. Collectively, these findings underscore the importance of HNF4A as a conserved transcription factor controlling IEC–IEL crosstalk and suggest that HNF4A maintains intestinal homeostasis through regulation of the IEL compartment.

Dysregulation of γδ intraepithelial lymphocytes precedes Crohn’s disease-like ileitis

“…Consistent with this, EdU incorporation was decreased and the frequency of apoptotic γδ IELs was increased in 5-week-old TNF ΔARE/+ mice relative to WT (Figure 2a-d). Epithelial butyrophilin proteins (BTNL) are critical for the maturation and development of γδ IELs 28 , and these genes were recently shown to be regulated by HNF4A and HNF4G transcription factors 29 . A reduction in Hnf4g was apparent at 4 weeks of age in the ilea of TNF ΔARE/+ mice, yet Hnf4a expression was not affected (Figure 2e).…”

CD90 is not constitutively expressed in functional innate lymphoid cells

“…Furthermore, Aspergillus fumigatus -induced inflammation also leads to the promoted occurrence of pulmonary CD4 + T cells with low expression of CD90 (Ulrich et al ., 2022). In the intestine, variable expression of CD90 can be observed in Vγ7 + intraepithelial lymphocytes in addition to conventional CD4 + and CD8 + T cells (Lei et al ., 2022, Lo et al ., 2022).…”

“…In relation to this, transition of CD90 low to CD90 high ILC2 precursors has been described using an in vitro model in which CLP were seeded, but again the role of the gain in CD90 is unknown (Seehus et al, 2014). Recently, it was reported that in the murine liver Ly49E + ILC1 have a lower expression of CD90 than Ly49E -ILC1 (Chen et al, 2022, Sparano et al, 2022.…”

“…Similarly to T and NK cells, ILC express the glycophosphatidylinositol (GPI) anchored protein CD90 in diverse tissues, and CD90 has often been used as a key marker to identify ILC (Sauzay et al, 2019, Leyton et al, 2019, Barman et al, 2021, Cox et al, 2021, Fachi et al, 2021, Ualiyeva et al, 2021, Xiao et al, 2022, He et al, 2022, Han et al, 2022, Peng et al, 2022, Chen et al, 2022, Wu et al, 2022a, Wu et al, 2022b, Glaubitz et al, 2022, Bruchard et al, 2022, Sheikh et al, 2022, Riding et al, 2022, Peng et al, 2022, Schmalzl et al, 2022, and CD90 has been used as key target to deplete ILC in Rag-deficient mice using a specific antibody (e.g. Powell et al, 2012, Mortha et al, 2014, Martin et al, 2017, Rafei-Shamsabadi et al, 2018, Castro-Dopico et al, 2020, Ray et al, 2022, Dobeš et al, 2022.…”

CD90 is not constitutively expressed in functional innate lymphoid cells

“…Furthermore, Aspergillus fumigatus -induced inflammation also leads to the promoted occurrence of pulmonary CD4 + T cells with low expression of CD90 ( 63 ). In the intestine, variable expression of CD90 can be observed in Vγ7 + intraepithelial lymphocytes in addition to conventional CD4 + and CD8 + T cells ( 64 , 65 ).…”