Intestinal γδ T Cells Develop in Mice Lacking Thymus, All Lymph Nodes, Peyer’s Patches, and Isolated Lymphoid Follicles

Abstract

Through analysis of athymic (nu/nu) mice carrying a transgenic gene encoding GFP instead of RAG-2 product, it has recently been reported that, in the absence of thymopoiesis, mesenteric lymph nodes and Peyer’s patches (PP) but not gut cryptopatches are pivotal birthplace of mature T cells such as the thymus-independent intestinal intraepithelial T cells (IEL). To explore and evaluate this important issue, we generated nu/nu mice lacking all lymph nodes (LN) and PP by administration of lymphotoxin-β receptor-Ig and TNF receptor 55-Ig fusion proteins into the timed pregnant nu/+ mice that had been mated with male nu/nu mice (nu/nu LNP− mice). We also generated nu/nu aly/aly (aly, alymphoplasia) double-mutant mice that inherently lacked all LN, PP, and isolated lymphoid follicles. Although γδ-IEL were slightly smaller in number than those in nu/nu mice, substantial colonization of γδ-IEL was found to take place in the intestinal epithelia of nu/nu LNP− and nu/nu aly/aly mice. Notably, the population size of a major CD8αα+ γδ-IEL subset was maintained, the use of TCR-γ-chain variable gene segments by these γδ-IEL was unaltered, and the development of cryptopatches remained intact in these nu/nu LNP− and nu/nu aly/aly mice. These findings indicate that all LN, including mesenteric LN, PP, and isolated lymphoid follicles, are not an absolute requirement for the development of γδ-IEL in athymic nu/nu mice.

Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

“…Taken together, these data indicate that IL-15 establishes permissive V γ 5 gene segment accessibility for directed gene rearrangement in both the thymus and intestine. Whether sufficient functional recombinase activity exists in the putative intestinal lymphoid precursors of normal mice is controversial 39,40 , but irrespective of anatomical sites, our results show that IL-15 programs targeted enhancement in V γ 5 gene accessibility conducive for selective gene rearrangement.…”

“…Recent findings have indicated the exclusive origin αβTCR + i-IELs from CD4 + CD8 + thymocytes in euthymic mice 4 , but the situation remains murky for γδ i-IELs. The developmental requirements for γδ i-IELs are distinct from those of αβ i-IELs 4,10 and suggestive evidence for the extrathymic development of γδ i-IELs exists 40,45 . However, in unperturbed normal mice, robust RAG1 and RAG2 expression is difficult to detect in the gut 39 .…”

“…This scenario is reminiscent of the V γ 3 + γδ dendritic epidermal T cells that arise in the thymus via a programmed gene rearrangement exclusively during the fetal stage, which are positively selected in the thymus to acquire the skin homing ability 46 . Hence, despite the fact that immature lymphoid cells in both the thymus and intestine are governed similarly by IL-15 to become preferentially poised to generate V γ 5-expressing cells, as assessed by histone acetylation patterns, and γδ i-IEL development is less compromised than αβ i-IELs in athymic mice 39,40 , the apparent paucity of RAG proteins in the gut of euthymic mice may prohibit substantial generation of γδ i-IELs in the intestine. Caveats to this interpretation are that there might be as yet unidentified intestinal niches where active Tcrg and Tcrd recombination does occur, but currently employed experimental assays are insensitive to detect such events and/or RAG1 and RAG2 are transiently expressed in the intestine in certain conditions, such as in neonatal stages or during acute infection of the gut to permit extrathymic γδ T cell development.…”

Severe Defect in Thymic Development in an Insertional Mutant Mouse Model

“…These thymus-independent T cells develop mainly in the intestine and liver and include certain subsets of TCR␣␤ ϩ and ␥␦ ϩ T cells (22). It has previously been shown that the numbers of thymus-independent T cells increase in parallel with thymic involution (23,24).…”

Detection and Characterization of Hemopoietic Stem Cells in the Adult Human Small Intestine

“…Although the majority of classical intestinal T cells arise in the thymus (15) and home to the gut, there is evidence that specialized T cell subsets develop locally in the intestine (14,16). If lymphoid development occurs in the intestine, precursors and factors required for their maturation should be present (14).…”