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

Abstract

Interactions between lymphotoxin (LT)α1β2 on inducer cells and the lymphotoxin β receptor (LTβR) on stromal cells initiate development of lymph nodes and Peyer’s patches. In this study, we assessed the contributions of LTα and LTβR to the development of cryptopatches (CP), aggregates of T cell precursors in the mouse small intestine. Mice genetically deficient in LTα or LTβR lacked CP. Bone marrow from LTα-deficient mice was unable to initiate development of CP or isolated lymphoid follicles (ILF) after transfer to CD132-null mice lacking CP and ILF. However, LTα-deficient bone marrow-derived cells contributed to CP formed in CD132-null mice receiving a mixture of wild-type and LTα-deficient bone marrow cells. Transfer of wild-type bone marrow into irradiated LTα-deficient mice resulted in reconstitution of both CP and ILF. However, the LT-dependent formation of CP was distinguished from the LT-dependent formation of ILF and Peyer’s patches by not requiring the presence of an intact NF-κB-inducing kinase gene. CP but not ILF were present in the small intestine from NF-κB-inducing kinase-deficient alymphoplasia mice, indicating that the alternate NF-κB activation pathway required for other types of LTβR-dependent lymphoid organogenesis is dispensable for CP development. In addition, we identified VCAM-1+ cells within both CP and ILF that are candidates for the stromal cells involved in receiving LT-dependent signals from the hemopoietic precursors recruited to CP. These findings demonstrate that interactions between cells expressing LTα1β2 and LTβR are a shared feature in the development of all small intestinal lymphoid aggregates.

Adaptation of Solitary Intestinal Lymphoid Tissue in Response to Microbiota and Chemokine Receptor CCR7 Signaling

“…Previous reports showed that ILF and CP can be induced in lymphotoxin ␣ mutants lacking such structures by transplantation with wild-type bone marrow (13,26). We therefore generated bone marrow chimeras using wild-type and CCR7-deficient mice as recipients and/or donors and analyzed the phenotype of SILT 7-9 wk after reconstitution.…”

“…We and others have reported previously that any type of lymphoid aggregation is absent in the intestine of lymphotoxin ␣ mutants (17,26). To further characterize the requirements of other signaling molecules expressed on LTIC for SILT organogenesis, we analyzed the phenotype of SILT in CCR7-deficient and plt/plt mice that lack the CCR7 ligands CCL19 and CCL21-Ser.…”

Chemokine Receptor CXCR5 Supports Solitary Intestinal Lymphoid Tissue Formation, B Cell Homing, and Induction of Intestinal IgA Responses

“…Like PP, SILT are absent in the intestines of lymphotoxin-␣, lymphotoxin-␤ and lymphotoxin-␤ receptor-deficient mice (4,18). Moreover, SILT, as well as PP, fail to form in mice lacking the orphan nuclear receptor ROR␥t, which is required for the development and maintenance of LTIC (19).…”

Lymphotoxin-Independent Expression of TNF-Related Activation-Induced Cytokine by Stromal Cells in Cryptopatches, Isolated Lymphoid Follicles, and Peyer’s Patches

“…We recently discovered a population of VCAM-1 ϩ stromal cells in both CP and ILF, identifying these cells as candidates for LT␤R-expressing cells involved in the development and maintenance of these structures (20). Because stromal cell populations in CP and ILF had not been previously described, we have characterized the phenotype and origin of these stromal cell populations in detail, focusing on defining what features of these stromal cell networks were dependent on LT signaling.…”

“…Like other lymphoid tissues, the formation of CP and ILF requires LT␣ 1 ␤ 2 signaling through the LT␤R. Studies using bone marrow (BM) chimera models have shown that the cellular source of LT␣ 1 ␤ 2 used to generate CP and ILF is within the hemopoietic compartment, whereas nonhemopoietic stromal cells provide the LT␤R (19,20).…”