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Daniel Cruz^*,, Beate C. Sydora^*,, Kristine Hetzel^*, Gian Yakoub^*,, Mitchell Kronenberg^*,,, and Hilde Cheroutre^*,

From the ^* Department of Microbiology and Immunology and the Division of Digestive Diseases, Department of Medicine, University of California at Los Angeles, Los Angeles, California 90095; and the La Jolla Institute for Allergy and Immunology, San Diego, California 92121

The differentiation of intestinal intraepithelial lymphocytes (IEL) remains controversial, which may be due in part to the phenotypic complexity of these T cells. We have investigated here the development of IEL in mice on the recombination activating gene (RAG)-2^–/– background which express a T cell antigen receptor (TCR) transgene specific for an H-Y peptide presented by D^b (H-Y/D^b x RAG-2^– mice). In contrast to the thymus, the small intestine in female H-Y/D^b x RAG-2^– mice is severely deficient in the number of IEL; TCR transgene⁺ CD8 and CD8β are virtually absent. This is similar to the number and phenotype of IEL in transgenic mice that do not express the D^b class I molecule, and which therefore fail positive selection. Paradoxically, in male mice, the small intestine contains large numbers of TCR⁺ IEL that express high levels of CD8 homodimers. The IEL isolated from male mice are functional, as they respond upon TCR cross-linking, although they are not autoreactive to stimulator cells from male mice. We hypothesize that the H-Y/D^b TCR fails to undergo selection in IEL of female mice due to the reduced avidity of the TCR for major histocompatibility complex peptide in conjunction with the CD8 homodimers expressed by many cells in this lineage. By contrast, this reduced TCR/CD8 avidity may permit positive rather than negative selection of this TCR in male mice. Therefore, the data presented provide conclusive evidence that a TCR which is positively selected in the thymus will not necessarily be selected in IEL, and furthermore, that the expression of a distinct CD8 isoform by IEL may be a critical determinant of the differential pattern of selection of these T cells.

Key Words: T cells • intraepithelial lymphocytes • positive selection • coreceptors

Abbreviations used: IEL, intestinal intraepithelial lymphocyte(s); DN, double negative; LPL, lamina propria lymphocyte(s); RAG, recombination activating gene; TAP, transporter associated with antigen processing.

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