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

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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.