Natural killer (NK) cell development is thought to occur in the bone marrow. Here we identify the transcription factor GATA-3 and CD127 (IL-7R alpha) as molecular markers of a pathway of mouse NK cell development that originates in the thymus. Thymus-derived CD127+ NK cells repopulated peripheral lymphoid organs, and their homeostasis was strictly dependent on GATA-3 and interleukin 7. The CD127+ NK cells had a distinct phenotype (CD11b(lo) CD16- CD69(hi) Ly49(lo)) and unusual functional attributes, including reduced cytotoxicity but considerable cytokine production. Those characteristics are reminiscent of human CD56(hi) CD16- NK cells, which we found expressed CD127 and had more GATA-3 expression than human CD56+ CD16+ NK cells. We propose that bone marrow and thymic NK cell pathways generate distinct mouse NK cells with properties similar to those of the two human CD56 NK cell subsets.

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...

SummaryMouse gut intraepithelial lymphocytes (IEL) consist mainly (90%) of two populations of CD8+ T cells . One bears heterodimeric ct/0 CD8 chains (Lyt-2+, Lyt-3+), a T cell receptor (TCR) made of ac/(3 chains, and is Thy-1+ ; it represents the progeny of T blasts elicited in Peyer's patches by antigenic stimulation. The other bears homodimeric cx/a CD8+ chains, contains no a chain mRNA, and is mostly Thy-1 -and TCIt-y/S+ or -ci/)3+ ; it is thymo-independent and does not require antigenic stimulation, as shown by its presence: (a) in nude and scid mice; (b) in irradiated and thymectomized mice repopulated by T-depleted bone marrow cells bearing an identifiable marker ; (c) in thymectomized mice treated by injections of monoclonal anti-CD8 antibody, which lead to total depletion of peripheral CD8+ T lymphocytes ; and (d) in germfree mice and in suckling mice . In young nude mice, cx/a CD8 chains, CD3 TCR complexes, and TCR mRNAs (first , y/6) are found on IEL, while they are not detectable on or in peripheral or circulating lymphocytes or bone marrow cells . IEL, in contrast to mature T cells, contain mRNA for the RAG protein, which is required for the rearrangement of TCR and Ig genes. We propose that the gut epithelium (an endoderm derivative, as the thymic epithelium) has an inductive property, attracting progenitors of bone marrow origin, and triggering their TCR rearrangement and cx/u CD8 chains expression, thus giving rise to a T cell population that appears to belong to the same lineage as y/6 thymocytes and to recognize an antigenic repertoire different from that of u/(3 CD8+ IEL.

CC chemokine receptor (CCR) 9, the receptor for the CC-chemokine CCL25/ thymus-expressed chemokine (TECK), is mainly expressed by thymocytes and by intraepithelial (IEL) and lamina propria lymphocytes of the small intestine. To study the biologic role of CCR9, a mouse strain was generated in which the CCR9 gene was deleted. In spite of the high level of CCR9 found in double-and singlepositive thymocytes and of the expression of its corresponding ligand on thymic stromal cells, CCR9 deletion had no major effect on intrathymic T-cell development. It was noted that there was only a one-day lag in the appearance of doublepositive cells during fetal ontogeny in CCR9 ؊/؊ thymi. When tested in chemotaxis assay, thymocytes isolated from CCR9 ؊/؊ mice failed to respond to TECK/ CCL25. Taken together, these results suggest that in thymocytes, CCR9 is the only physiologic receptor for TECK/CCL25, and that it is dispensable for proper T-cell development. Bone marrow pre-pro-B cells migrate in response to TECK/CCL25, but more mature B cells do not. Consistent with this observation, it was shown that there are fewer pre-pro-B cells in CCR9 ؊/؊ mice than in wild-type mice. However, this diminution does not appear to have a detectable effect on the generation of a normal complement of mature B cells. Finally, it was shown that in the small intestine of CCR9-deficient mice, the intraepithelial T-cell-to-epithelial cell ratio is decreased, an observation that can be accounted for by a marked diminution of the T-cell receptor ␥␦ ؉ compartment. IntroductionDuring their development in the thymus, T cells migrate from the outer capsule to the inner medulla, a process that allows their sequential interaction with different types of stromal cells. Following their exportation to the periphery, a sophisticated network of chemokines control their appropriate navigation to and from secondary lymphoid organs. [1][2][3] Likewise, the migration of developing T and B cells within their respective primary lymphoid organs is likely under the control of chemokines. 4,5 Consistent with the implication of G protein-coupled chemokine receptors in the intrathymic trafficking of T cells, the latter is inhibited by pertussis toxin. 6 Moreover, developing thymocytes express several chemokine receptors and their corresponding ligands produced by thymic stromal cells. 7 Recent studies, including our own, have described a novel thymus-expressed chemokine (TECK)/CCL25 8,9 and its receptor, CC chemokine receptor 9 (CCR9). 9-12 TECK/CCL25 is predominantly expressed by most thymic epithelial cortical cells, by a few thymic epithelial medullary cells, and by CD11b Ϫ thymic dendritic cells. 9,13 The level of CCR9 transcripts undergoes a 10-fold increase during the double-negative (DN) to double-positive (DP) transition. Among thymocytes, DP thymocytes have the highest CCR9 expression and this correlates with their ability to migrate in response to TECK/CCL25. CCR9 transcripts subsequently decrease in single-positive (SP) thymocytes. Therefore, TECK/ CCL25 may d...

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A monoclonal antibody, HML-1, was produced by fusion of NSI myeloma cells with spleen cells of a mouse immunized with isolated human intestinal intraepithelial lymphocytes (IEL). Immunofluorescence studies of isolated cells, as well as immunoperoxidase staining of tissue sections, indicated that HML-1 labeled all the various subsets of human intestinal IEL, approximately 40% of lamina propria T cells, 30% mesenteric lymphoblasts and some lymphocytes in other mucosae, particularly IEL. Conversely, it revealed only rare cells in all other lymphoid compartments. Analysis by polyacrylamide gel gradient electrophoresis showed that HML-1 precipitated two major noncovalently bound components of approximate mol. masses of 105 and 150 kDa from human IEL. HML-1 thus defines a novel human membrane antigen present on a subpopulation of lymphocytes preferentially associated with epithelia, and particularly with the intestinal epithelium. The characteristics of this human antigen are very similar to those of an antigen we had previously described in the rat. The possible functional role of this novel class of lymphocyte membrane antigens as well as the nature of the mechanism that triggers their expression remain to be elucidated.

The gut epithelium favors the development of T cells that express NK receptors. In active celiac disease, there is a specific and selective increase of IELs expressing CD94, the HLA-E-specific NK receptor that may be related to T-cell receptor activation and/or interleukin 15 secretion.