Requirement for Lymphoid Tissue-Inducer Cells in Isolated Follicle Formation and T Cell-Independent Immunoglobulin A Generation in the Gut

Abstract

Immunoglobulin A (IgA) is generated in the gut by both T cell-dependent and T cell-independent processes. The sites and the mechanisms for T cell-independent IgA synthesis remain elusive. Here we show that isolated lymphoid follicles (ILFs) were sites where induction of activation-induced cytidine deaminase (AID) and IgA class switching of B cells took place in the absence of T cells. We also show that formation of ILFs was regulated by interactions between lymphoid tissue-inducer cells expressing the nuclear receptor ROR gamma t (ROR gamma t(+)LTi cells) and stromal cells (SCs). Activation of SCs by ROR gamma t(+)LTi cells through lymphotoxin (LT)-beta receptor (LT beta R) and simultaneously by bacteria through TLRs induced recruitment of dendritic cells (DCs) and B cells and formation of ILFs. These findings provide insight into the crosstalk between bacteria, ROR gamma t(+)LTi cells, SCs, DCs, and B cells required for ILF formation and establish a critical role of ILFs in T cell-independent IgA synthesis in gut.

Generation of colonic IgA-secreting cells in the caecal patch

“…1f). As previously reported, Peyer's patch cells from T-cell-deficient (Tcrb À / À Tcrd À / À ) mice produced lower, but substantial, amounts of IgA than those of the wild-type mice [26][27][28] ( Fig. 1g).…”

“…ILF has been shown to contribute to T-cell-independent IgA synthesis, the mechanism of which is different from that observed in Peyer's patches 26 . In addition, ILFs have been shown to increase in number in the small and large intestines of mice lacking CCR10, which show normal numbers of IgA-secreting cells in the intestine 17 .…”

“…ILFs are sites of generation of IgA-secreting cells with differential mechanisms to those from Peyer's patches 26 . In the absence of CCR10, SILTs including ILFs have been reported to enlarge and increase in number, which contributed to the maintenance of a normal number of IgA-secreting cells in the intestine of Ccr10 À / À mice 17 .…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Cryptopatch‐resident ILC3 maintain the local crypt stem cell pool and regulate tissue repair following inflammation, chemotherapy or transplantation 37, 38, 39. In addition, cryptopatches act as a site for B‐cell recruitment to form mature tertiary lymphoid structures known as isolated lymphoid follicules (ILFs) 36, 40, 41. ILFs are important sites for production of IgA against intestinal bacteria and ILF hyperplasia occurs in the context of inflammation or bacterial outgrowth,41 suggesting that ILFs are ILC3‐regulated inducible lymphoid tissues required for orchestration of local responses to commensal bacteria.…”

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

“…Hoechst 33342 dye was used to visualize nuclei. AID protein was detected using the monoclonal anti-AID antibody, MAID-2 (Tsuji et al, 2008), with peroxidase-labelled donkey F(ab 0 )2 anti-rat IgG (Jackson ImmunoResearch, West Grove, PA, USA) and signal amplification using TSA Plus DNP and TSA Plus TMR kits (Perkin Elmer, Waltham, MA, USA). Images taken with a fluorescence microscope (DM5000B; Leica, Wetzlar, Germany) were merged using Photoshop (Adobe, San Jose, CA, USA).…”