Thymus-independent development and negative selection of T cells expressing T cell receptor alpha/beta in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes.

Abstract

SummaryWe demonstrate that mouse intestinal intraepithelial lymphocytes (IEL) can be divided into subsets based on the differential expression of functional T cell receptor r signaling complexes. Two subsets, CD4+8c~+fl -and CD8oL+~ -, are refractory to stimulation with anti-TCR-a/fl and contain high frequencies of potentially self-reactive cells. In contrast, the CD4 + and CD8a +B + IEL subsets are responsive to anti-TCR-o~/fl and depleted of potentially selfreactive cells. The analysis of fetal liver radiation chimeras using adult thymectomized recipients demonstrates that the four TCR-odB + IEL subsets are generated in normal numbers in the absence of the thymus. Moreover, expression of the major histocompatibility complex class II-encoded I-E molecule and Mlsl ~ in the gut of the athymic host results in the negative selection of potentially stir-reactive T cells expressing V/~11 and V/~6, respectively, from those IEL subsets that express functional TCR-cr signaling complexes. Neither the spleen nor the Peyer's patches of athymic recipients contain T cells of donor origin. In contrast, normal numbers of phenotypically and functionally mature CD4 + and CD8c~+fl + T cells of donor origin are found in the lamina propria of chimeric animals. The phenotypic analysis of lymphocytes obtained from Ly5 congenic parabionts reveals that peripheral T cells migrate rapidly to the Peyer's patches and lamina propria, but not to the intestinal epithelium. Taken together, these results demonstrate that the intestinal epithelium is a thymus-independent site of T lymphopoiesis, where selection of the T cell repertoire involves the deletion of potentially self-reactive cells in situ. Moreover, the appearance of donor-derived, phenotypically mature T ceils, exclusively in the lamina propria of athymic radiation chimeras, suggests that mature IEL expressing functional TCR-o~/fl migrate to this site.

Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice

“…These IELs contained Ͼ90% CD3 ϩ cells as determined by FACS analysis. LPLs were isolated by a modified version of published protocols (24,25). Briefly, following IEL isolation, residual epithelial cells were removed by shaking in PBS containing 1.3 mM EDTA at 37°C for 30 min.…”

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

“…For example, IEL are enriched with TCR-␥␦ T cells (6,7), and virtually all ␥␦-IEL and about one-third of ␣␤-IEL, unlike thymus-derived T cells that use -chain as part of their CD3 complex, express the unique CD8␣␣ homodimer (8 -11) instead of the CD8␣␤ heterodimer and can use the Fc receptor ␥-chain (12)(13)(14) in place of the -chain. Accumulating evidence indicates that these CD8␣␣ ϩ IEL are potentially capable of developing somewhere in the intestinal mucosa without passing through the thymus (9,(15)(16)(17)(18)(19)(20). Moreover, the presence of lymphoid cells with properties of precursor T cells among IEL (1,9,19,(21)(22)(23)(24) and the expressions of recombination activating gene-1 (RAG-1) (9,19,21) and RAG-2 (25) by a subset of IEL support the notion that T lineage-committed precursors may enter the epithelium and undergo all steps of TCR gene rearrangement and subsequent differentiation into mature IEL in situ.…”

The Influence of Age and Breeding Conditions on the Number and Proliferation of Intraepithelial Lymphocytes in Pigs

“…After oral administration of cholera toxin the uptake of BrdU increased severalfold [12]. In parabiosis, after 5 weeks only very few cells had migrated from one animal to the gut epithelium of the other animal, indicating a long life span or low rate of replacement [13]. Studies using tritiated thymidine [14,15] indicated that only a small fraction of IEL proliferate locally and some IEL are long-lived.…”