Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain.

Abstract

The interleukin 2 receptor y chain (IL-2R'y) is a component of the receptors for IL-2, IL-4, IL-7, and IL-15. Mutations in IL-2Ry in man appear responsible for the X chromosome-linked immunodeficiency SCIDX1, characterized by a defect in T-cell and natural killer (NK)-cell differentiation with the presence of poorly functioning B cells. To explore at which level IL-2Ry affects lymphoid development in vivo, we have analyzed mice derived from embryonic stem (ES) cells with mutant IL-2Ry loci generated by Cre/loxPmediated recombination. In the peripheral blood of chimeric animals, lymphoid cells derived from IL-2Ry-ES cells were not detected, although control ES cells carrying an IL-2R'y gene with embedded loxP sites gave rise to T-, B-, and NK-cell lineages. Germline IL-2Ry-deficient male animals, however, developed some mature splenic B and T cells, although the absolute number of lymphocytes was almost 10-fold reduced. In contrast, there was a complete disappearance of NK cells (over 350-fold reduction). Development of gut-associated intraepithelial lymphocytes was also severely diminished, and Peyer's patches were not detected. In vitro mitogenic responses of thymocytes, IL-4-directed immunoglobulin class switch of splenocytes, and NK activity were defective. Thus, IL-2Ry facilitates mainstream B-and T-cell generation and function and also appears to be essential for NK-cell development.Lymphoid development results from the expansion and differentiation of committed precursor cells under the influence of the bone marrow, thymic, and gut microenvironments, which requires both stem cell-stromal cell contact and interactions between soluble cytokines and their receptors (1, 2). The interleukin 2 receptor y chain (IL-2Ry), initially identified as an effector component of the IL-2R (3), figures prominantly in lymphopoiesis, through its participation in the receptors for IL-2, IL-4, IL-7, and IL-15 (4-8). Severe combined immunodeficiency Xl (SCIDX1), an X chromosomelinked immunodeficiency characterized by a severe block in T-cell and NK-cell differentiation with the presence of normal or elevated numbers of poorly functioning B cells (9, 10), is associated with mutations in IL-2Ry (11). Still, the level at which IL-2Ry mutations disrupt normal cytokine/receptor function and cause SCIDX1 is not known.A variety of lymphokines play a role in the early stages of lymphoid development. In mice, in vivo blockade of the IL-7/IL-7R system with antibodies results in a complete block in B-cell generation and a substantial decrease in T lymphopoiesis (12, 13). In contrast, mice deficient for IL-2, IL-4, or both lymphokines have normal numbers of mature B and T cells (14-16). Therefore the phenotype in human SCIDX1 (near absence of T cells, elevated proportions of B cells) cannot be easily explained by defects in the IL-2, IL-4, or IL-7 receptor systems, without a species-specific difference in receptor function. In addition, the use of IL-2Ry in additional cytokine receptors (such as IL-15R and perhaps others) and the r...

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

“…Consistent with the results obtained from CR␥ Ϫ/Y (31, 32) and CR␥ null mutant (28,29) mice, PP and peripheral lymph nodes, except markedly atrophied MLN, were not detectable in athymic CR␥ Ϫ/Y mice at necropsy. We also examined MLN cells and spleen cells isolated from athymic CR␥ Ϫ/Y mice and found that a TCR Ϫ lymphocyte population that expressed c-kit, Thy-1, CD4, and CD8␣␤ molecules was present exclusively in the IEL compartment (Fig.…”

“…1A). Severely diminished development of IEL in CR␥ mutant mice has also been reported (28,29). Surprisingly, we found that lymphoid cell aggregates filled with a meaningful number of c-kit ϩ cells, namely CP, were hardly detectable in the intestinal LP of CR␥ Ϫ/Y mice and that most c-kit ϩ cells were localized individually throughout the length of the small intestine, although two to three c-kit ϩ cells settled together in several locations (Fig.…”

“…In the null mutant mice, development of IEL is severely diminished and PP are not detected (28,29). We examined extensively tissue sections of small intestine prepared from male mice with a truncated mutant of the CR␥ chain (CR␥ Ϫ/Y mice) that showed a phenotype similar to that of the null mutant mice in terms of development of the lymphocyte population (31,32) and verified that CP were undetectable.…”

Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

“…Several signals have been implicated in controlling thymopoiesis including those emanating from the TCR following interactions with self-peptide1MHC (pMHC) and those induced by growth factors including cytokines [12]. Mice lacking the common cytokine receptor gamma chain (g c ) family of cytokines (which comprise IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21) have hypoplastic thymi and a reduced number of T cells, although the T cells generated were able to respond to a range of mitogens [33,34]. Humans possessing mutations in genes encoding the g c , Jak3 (both critical for signal transduction following binding g c cytokines) or the a chain of the IL-7 receptor (IL-7Ra), also display a severe block in T-cell development and resulting severe combined immunodeficiency [35].…”

Identification of the primary outcomes that result from deficient spiral arterial modification in pregnant mice

“…BALB/c +/+ weights at weeks [10][11][12][13][14][15][16], that were statistically less than agematched weights of Rag2 −/− /Il2rg −/− , are measurements on animals in our care. At 10 weeks of age, female Rag2 −/− /Il2rg −/− mice were on average 3.2 g heavier that BALB/c mice (P<0.001), a finding that had implications for our anaesthetic protocol and overall postsurgical success for surgical implantation of radiotransmitters in BALB/c control mice (see below).…”