Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop.

Abstract

SummaryWe have revealed that about one and a half thousand tiny clusters, filled with one thousand closely packed lymphocytes, can be found throughout the murine small and large intestinal nmcosa. They are located in crypt lamina propria (cryptopatches; CP) and can be first detected at 14-17 d after birth. A large fraction oflymphocytes in CP expresses c-kit, IL-7R, Thyl and a lymphocyte function-associated antigen, LFA-1, whereas most of them remain CD3-, TCR oil3-, TCR "yS-, slgM-, and B220-. The population size of IL-2Ikot +, HSA + and Pgp-1 + subsets is variable (20-50%) and the composition of CD8 +, Ly-1 +, and CD4 + subsets is smaller but also variable (3-20%). In the small intestine, CP do not contain cells undergoing apoptosis nor cells bearing RAG-1 molecules, but do contain dendritic stromal cells bearing CD1 lc/CD18 molecules. The frequency of DNA replicating cells in CP is higher than that in Peyer's patches (PP), is lower than that in the thymic cortex and is almost comparable with that in the thymic medulla. The numbers of CP remain the same in aged mice (>114 wk) but double after estrogen treatment even though the thymi are attenuated sharply in both conditions. Thus, with respect to histogenesis, lymphocyte composition and tissue level of cellular behavior, neither PP, isolated lymphoid follicles, peripheral LNs, nor thymus are identical with CP. Finally, CP are virtually absent in lamina propria of IL-7R-deficient mice that display a profound reduction in thymic and peripheral lymphoid cellularity. By contrast, CP are present in germ-free mice and in athymic (nu/nu), SCID, TCR [3 • 8-/-, RAG-2 -/-, PP-deficient (aly/aly), stem cell factor (S1/S1 a) and c-kit (W/W v) mutant mice. Taking all of these results together, CP are the first identification of gut-associated murine lymphoid tissues where the generation of IL-7-dependent lympho-hematopoietic progenitors for T and/or B cell descendants may start to take place at the age of commencement of weaning.

A Role for CCR9 in T Lymphocyte Development and Migration

“…Cryptopatches are multiple clusters of c-kit ϩ IL-7R ϩ Thy1 ϩ lymphocytes located in the crypt lamina propria of the murine intestine (45). CCR9 may be involved in cryptopatch formation and/or extrathymic ␥␦TCR ϩ IEL development, perhaps by regulating the migration of progenitor cells from the fetal liver, fetal thymus, or adult bone marrow to the small intestine.…”

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

“…18 The Density and Distribution of CD11c ϩ Cells Are Not Perturbed in RANKL Ϫ/Ϫ CP CD11c ϩ dendritic cells account for 20% to 30% of the cells in the small intestinal CP of adult mice. 7 These CD11c ϩ cells are concentrated at the border of CPs, with the Thy-1 ϩ LTi cells predominating centrally. 7,21 During the postnatal development of CP, clusters of CD11c ϩ cells associate with CP before the influx of B cells to generate ILF begins.…”

“…7 These CD11c ϩ cells are concentrated at the border of CPs, with the Thy-1 ϩ LTi cells predominating centrally. 7,21 During the postnatal development of CP, clusters of CD11c ϩ cells associate with CP before the influx of B cells to generate ILF begins. 22 We examined the distribution of CD11c ϩ cells in RANKL Ϫ/Ϫ CPs to ascertain whether a failure to recruit normal numbers of CD11c ϩ cells or a perturbation in the distribution of CD11c ϩ cells might be a contributor to the failure of RANKL Ϫ/Ϫ CPs to progress to ILF development.…”

“…Although CPs are present in germ-free mice, the development of ILFs in the small intestine from these precursor CPs requires signals originating with the commensal enteric flora. 7,[12][13][14] We have previously shown that RANKL is expressed on stromal cells found throughout CPs, but is preferentially expressed by stromal cells located in the subepithelial dome of ILFs and PPs. 15 We also showed RANKL appears on stromal cells later in ontogeny than other stromal cell antigens including the follicular dendritic cell marker FDC-M1, vascular cell adhesion molecule 1 (VCAM-1), and CD157, and can still be induced when LT␣ 1 ␤ 2 signaling through the LT␤R is blocked.…”

Intestinal Cryptopatch Formation in Mice Requires Lymphotoxin α and the Lymphotoxin β Receptor

“…Lymphotoxin ␣ and the Lymphotoxin ␤ Receptor 1 C ryptopatches (CP) 3 are aggregates of immature T cell precursors that develop postnatally and are found adjacent to crypts in the mouse small intestine (1). These T cell precursors are c-kit ϩ , IL-7R␣ ϩ , and Thy-1 ϩ and are in close contact with CD11c ϩ dendritic cells concentrated at the periphery of the CP (1).…”