Generation of intestinal mucosal lymphocytes in SCID mice reconstituted with mature, thymus-derived T cells (original) (raw)
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Identification and characterization of lymphoid precursors in the murine intestinal epithelium
European Journal of Immunology, 2001
Although in vivo evidence supports a role for the murine intestinal epithelium in the extrathymic generation of certain intraepithelial T lymphocytes (IEL), no intraepithelial cells with in vitro lymphoid progenitor potential have yet been demonstrated. Using reaggregate fetal thymic organ culture techniques, we show that a subset of CD3cells isolated from the intestinal epithelium of young mice is capable of generating T cells (§ g and +ˇ) and NK1.1 + cells in vitro. A novel IEL subset bearing a low level of CD45 was identified and found to comprise cells expressing highly immature lymphoid markers including CD34, c-kit, CD122, CD127 and high levels of CD16 and CD44. This subset represents 20-30% of intraepithelial CD45 + cells from 4-week-old wild-type and nude mouse strains and contains cells with in vitro T cell differentiation capacity. The identification of such an early pluripotent precursor phenotype within the intestinal epithelium implies that the potential for T cell generation exists at this site, and suggests that extrathymic T cell generation may occur within the epithelium itself.
Journal of Experimental Medicine, 1992
Adult athymic, lethally irradiated, Fl -parent bone marrow-reconstituted (AT x BM) mice were engrafted bilaterally with day 16-18 fetal intestine or fetal thymus into the kidney capsule and were studied for evidence of peripheral T cell repopulation of 1-12 wk postengraftment . Throughout that time period, both types of grafts were macroscopically and histologically characteristic of differentiated thymus or intestine tissues, respectively. Beginning at week 2 postengraftment, clusters of lymphocytes were present within intestine grafts, particularly in subepithelial regions and in areas below villus crypts . As determined by immunofluorescence staining and flow cytometric analyses, lymphocytes from spleen and lymph nodes of sham-engrafted mice (AT x BM-SHAM) were essentially void of T cells, whereas in AT x BM thymus-engrafted (AT x BMTHG) mice, which served as a positive control for T cell repopulation, normal levels of T cells were present in spleen and lymph nodes by week 3 postengraftment, and at times thereafter. Most striking, however, was the finding that T cell repopulation of the spleen and lymph nodes occurred in AT x BM fetal intestine-engrafted (AT x BM-FIG) mice beginning 3 wk postengraftment . Based on H-2 expression, peripheral T cells in AT x BM-FIG mice were of donor bone marrow origin, and consisted of CD3+, T cell receptor (TCR)-a/R+ T cells with both CD4+8 -and CD4 -8+ subsets . Peripheral T cells in AT x BM-FIG mice were functionally mature, as demonstrated by their capacity to proliferate after stimulation of CD3e . Moreover, alloreactive cytotoxic T lymphocytes were generated in primary in vitro cultures of spleen cells from AT x BM-FIG and AT x BMTHG mice, though not in spleen cell cultures from AT x BM-SHAM mice . Histologic studies of engrafted tissues 3-4 wk postengraftment
The thymus chapter in the life of gut-specific intra epithelial lymphocytes
Current Opinion in Immunology, 2008
The intestinal intraepithelial lymphocytes (IEL) represent multilineage T cell populations. In addition to a major gdTCR + T cell subset, many IEL express abTCRs and they can be separated into ab sublineages. Some TCRab + IEL have characteristics in common with conventional TCRab + T cells whereas others share an unconventional phenotype with their TCRgd + counterparts. Because the latter are enriched for autoreactive TCRs and can be generated in the absence of a thymus, it has long been postulated that some IEL subsets develop locally in the intestine. Several new data however, indicate that under physiological conditions, IEL require a thymic education that directs lineage commitment and functional differentiation. This review will discuss the contributions of the thymus in shaping the various intestinal IEL sublineages.
European Journal of Immunology, 1990
T cell receptor-bearing cells among rat intestinal intraepithelial lymphocytes are mainly a/P+ and are thymus dependent* Rearrangement of both the fi and y chainTcell receptor (TcR) genes was detected in intestinal intraepithelial lymphocytes (IEL) from normal euthymic rats. Flow cytometric analyses showed that about 73% of the IEL were CD3+ (1F4) and that 67% were TcR a@+ (R73). About 5% of the IEL were found to be CD3+, TcR dfiin double-labeling experiments suggesting that a small fraction of IEL in the rat express the alternative TcR y/S. More than 70% of the IEL were granular implying that many CD3+ IEL are granular. In IEL from athymic nude rats no rearrangement of either the TcR p or y chain genes or surface expression of CD3 or TcR dfi was detected despite the fact that about 95% of the cells were granular and morphologically similar to those in normal rats. Taken together our data suggest that the majority of IEL in the rat express the conventional TcR df3 and that TcR-bearing cells in the gut epithelium are thymus dependent..
2020
SummaryThe gut epithelium is populated by intraepithelial lymphocytes (IELs), a heterogeneous T cell population with cytotoxic and regulatory properties. Migrating peripheral CD4+ T cells, including regulatory (Treg) and conventional T cells (Tconv), acquire an IEL (CD4-IEL) program upon arrival at the epithelium. However, the specific role of the T cell receptor (TCR) in this process remains unclear. Single-cell TCR repertoire and transcriptomic analysis of intraepithelial CD4+ T cells revealed different extents of clonal expansion and TCR overlap between cell states; fully differentiated CD4-IELs from Tregs or Tconvs were the least diverse. Conditional deletion of TCR on differentiating CD4+ T cells or of MHCII on intestinal epithelial cells prevented CD4-IEL differentiation. However, TCR ablation on developed CD4-IELs did not affect their accumulation. These results indicate that local recognition of a limited set of antigens is an essential signal for the differentiation and ada...
The Journal of Immunology
Compared with T lymphocytes from other organs, intestinal intraepithelial lymphocytes (IEL) proliferate weakly in response to CD3/TCR ligation, and they do not respond at all to treatment with other mitogenic stimuli. These signals also failed to induce expression of the IL-2R alpha-chain on the surface of most IEL. IEL from germ-free mice, from V gamma 1.1-transgenic mice, and from beta 2-microglobulin-deficient mice also gave a weak proliferative response. Therefore, the low proliferative response is not linked to the level of exposure to gut bacterial flora, the V gamma region expressed by the TCR-gamma delta + IEL, or the presence of class I molecules that may be recognized by CD8+ IEL. The relatively small amount of proliferation in response to TCR signaling, therefore, is not likely to be the result of induction of anergy caused by previous contact with Ag. In contrast, ligation of the CD3/TCR complex could elicit a rapid cytotoxic response and serine esterase release by IEL. ...
Journal of Experimental Medicine, 1978
Lymphocytes of the mouse intestinal mucosa, identified in tissue sections or purified suspensions of intraepithelial lymphocytes as T cells (gut T lymphocytes [GTL]), were studied in normal mice or in beige mice (the equivalent of the Chediak-Higashi syndrome in man, characterized by giant granules in various cell types, including mast cells). Mice were studied in normal or in germ-free conditions, or during a graft versus host (GVH) reaction resulting from the injection of parental thymocytes into lethally irradiated F1 mice, a condition leading to massive accumulation of T lymphocytes of donor origin in the host gut mucosa. In normal as well as in GVH conditions, a high percentage of the gut IE lymphocytes contain granules (up to 80% in the beige mouse). These granules have ultrastructural, hostochemical and other features resembling those of mast cell granules; in beige mice, up to 50% of them can be shown to contain histamine. Granulated T cells are also found in the lamina prop...