Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain

Lympho-hemopoietic progenitors residing in murine gut cryptopatches (CP) have been shown to generate intestinal intraepithelial T cells (IEL). To investigate the role of CP in progenitor maturation, we analyzed IEL in male mice with a truncated mutation of common cytokine receptor γ-chain (CRγ−/Y) in which CP were undetectable. IEL-expressing TCR-γδ (γδ-IEL) were absent, and a drastically reduced number of Thy-1highCD4+ and Thy-1highCD8αβ+ αβ-IEL were present in CRγ−/Y mice, whereas these αβ-IEL disappeared from athymic CRγ−/Y littermate mice. Athymic CRγ−/Y mice possessed a small TCR- and αEβ7 integrin-negative IEL population, characterized by the disappearance of the extrathymic CD8αα+ subset, that expressed pre-Tα, RAG-2, and TCR-Cβ but not CD3ε transcripts. These TCR− IEL from athymic CRγ−/Y mice did not undergo Dβ-Jβ and Vδ-Jδ joinings, despite normal rearrangements at the TCR-β and -δ loci in thymocytes from euthymic CRγ−/Y mice. In contrast, athymic severe combined immunodeficient mice in which CP developed normally possessed two major TCR−αEβ7+ CD8αα+ and CD8− IEL populations that expressed pre-Tα, RAG-2, TCR-Cβ, and CD3ε transcripts. These findings underscore the role of gut CP in the early extrathymic maturation of CD8αα+ IEL, including cell-surface expression of αEβ7 integrin, CD3ε gene transcription, and TCR gene rearrangements.

Section: N Umerous Intraepithelial T Cells (Iel)mentioning

confidence: 99%

Role of Gut Cryptopatches in Early Extrathymic Maturation of Intestinal Intraepithelial T Cells

Oida

Suzuki

Nanno

et al. 2000

“…CD132-null mice (B6.129S4-IL2rg tm1Wjl /J) (17), LT␣ Ϫ/Ϫ mice (B6.129S2-Lta tm1Dch /J) (5), and TNFRI/TNFRII Ϫ/Ϫ mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Breeding colonies of the CD132-null and LT␣ Ϫ/Ϫ mice were maintained in a conventional mouse facility at Emory University.…”

Section: Micementioning

confidence: 99%

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

Taylor

Lügering

Newell

et al. 2004

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.

“…Studies of gene-targeted mice have provided much of the evidence implicating specific cytokines in ␣␤ T cell, ␥␦ T cell, or NK cell development. For instance, mice lacking IL-7 or components of the IL-7R signaling pathway (i.e., IL-7R␣, common ␥-chain (␥c), 3 or Jak3) fail to develop ␥␦ T cells (1)(2)(3)(4)(5)(6)(7). IL-15R signaling has been shown to be critical for NK cell development, as IL-15R␣-, ␥c-, and Jak3-deficient mice all lack NK cells (4 -10).…”

Section: A Profound Deficiency In Thymic Progenitormentioning

confidence: 99%

A Profound Deficiency in Thymic Progenitor Cells in Mice Lacking Jak3

Baird

Lucas

Berg

2000

Humans and mice with genetic deficiencies that lead to loss of signaling through common γ-chain (γc)-containing cytokine receptors have severe defects in B and T lymphocytes. In humans, these deficiencies lead to a complete absence of T cells, whereas in mice, small thymuses give rise to normal numbers of peripheral T cells. We have examined the first wave of developing T cells in Jak3−/−, IL-7−/−, and IL-7Rα−/− fetal mice, and have found a near absence of thymic progenitor cells. This deficiency is highlighted by the complete inability of Jak3−/− progenitor cells to reconstitute T cell development in the presence of competing wild-type cells. These data clearly demonstrate a strong common basis for the T cell deficiencies in mice and humans lacking γc/Jak3 signaling pathways.