Distinct Developmental Requirements for Isolated Lymphoid Follicle Formation in the Small and Large Intestine

Abstract

Cryptopatches (CPs) and isolated lymphoid follicles (ILFs) are organized intestinal lymphoid tissues that develop postnatally in mice and include stromal cells expressing the receptor activator of nuclear factor kappa-B ligand (RANKL). We investigated how stromal RANKL influences the development and differentiation of CPs and ILFs by analyzing the development of these lymphoid structures in knockout mice lacking RANKL. We found that RANKL ؊/؊ mice had a fourfold reduction in the overall density of CPs in the small intestine compared to control mice, with the largest decrease in the proximal small intestine. No B cells were present in CPs from the small intestine of RANKL ؊/؊ mice and ILF formation was completely blocked. In sharp contrast, colonic ILFs containing B cells were present in RANKL ؊/؊ mice. Stromal cells within CPs in the small intestine of RANKL ؊/؊ mice did not express CXCL13 (originally called B lymphocyte chemoattractant) and often lacked other normally expressed stromal cell antigens, whereas colonic lymphoid aggregates in RANKL ؊/؊ mice retained stromal CXCL13 expression. The CXCL13-dependent maturation of precursor CPs into ILFs is differentially regulated in the small intestine and colon, with an absolute requirement for RANKL only in the small intestine.

Guarding the perimeter: protection of the mucosa by tissue-resident memory T cells

“…Isolated lymphoid follicles, which develop after birth, can fulfill similar functions in the small intestine and colon. 28,29 In addition, a string of encapsulated MLNs is connected to the afferent lymphatics of the PPs and lamina propria (LP), where migratory cells (DC and lymphocytes) collect after they leave the intestinal tissues (Figure 1). 13,30 …”

RANKL coordinates multiple osteoclastogenic pathways by regulating expression of ubiquitin ligase RNF146

“…These results indicate that RANKL provides a dichotomous signal mediated through 2 distinct receptor systems to control osteoclastogenesis. In addition to the developmental effects of RANKL on osteoclastogenesis, lymph node and lymphocyte development, and breast epithelial proliferation (1)(2)(3)(4)(5)(6), recent studies show a link between RANKL and cancer development. The RANKL/RANK pathway mediates breast cancer driven by progestin, which is commonly used for hormone replacement therapy and contraceptives (39).…”

“…RANKL, a member of the TNF superfamily of cytokines, is an obligate factor required for osteoclast differentiation and survival, lymph node organogenesis, lymphocyte development, and breast epithelial proliferation (1)(2)(3)(4)(5)(6). Mice deficient in RANKL develop severe osteopetrosis due to low bone turnover as a result of absent functional osteoclasts (3).…”

Subclinical gut inflammation in ankylosing spondylitis

“…Aggregates of LTi in the small intestine of patients with AS were observed in close proximity to intestinal crypts [51 && ]. These structures, highly suggestive for cryptopatches, have been hypothesized to be sites of active postnatal extrathymic T cell development (as a consequence of intestinal bacteria colonization) and demonstrated only in the colon in humans [52,53]. Aggregates of c-kit þ Thy-1 þ CD3 -cells were, however, demonstrated in the ileum of AS patients, in close proximity to intestinal crypts.…”