Tolerance of T Cell Receptor γ/δ Cells in the Intestine

The present study examined the mechanism(s) of tolerance induction for intestinal intraepithelial lymphocytes (ilELs) using an alloantigen (Ag)-specific γ/δ T cell receptor (TCR γ/δ) transgenic (Tg) model. In Tg Ag-bearing H-2 ^b/d mice (Tg^b/d), Tg ilELs were Thy-l⁻, CD44⁺, CD45R (B220)⁺, and CD5⁺, whereas in syngeneic Tg a/d mice, ilELs were Thy-1⁺, CD44⁻, and CD45R- with a subset of CD5⁺ cells. Previously, we had shown that tolerance for Tg ^b/d ilELs involved functional anergy and deletion (Barrett, T. A., M. L. Delvy, D. M. Kennedy, L. Lefrancois, L. A. Matis, A. L. Dent, S. M. Hedrick, and J. A. Bluestone. 1992. J. Exp. Meal. 175:65). In this study we demonstrate that Tg ^b/d ilELs expressing dull levels of Thy-1 proliferated in the presence of exogenous rlL-2. A direct precursor-product relationship between the Thy-1⁺- responsive ilELs and the tolerant Thy-1^dul/− ilELs was demonstrated by adoptive transfer into severe combined immunodeficient (SCID) mice. Tg Thy-1⁺ ilELs reconstituting Ag⁺, but not Ag⁻ SCID mice downregulated Thy-1 after Ag exposure in vivo. Analysis of bone marrow (BM) chimeras demonstrated the persistence of Tg IELs in all Ag⁺ chimeras although a modest degree of clonal deletion was apparent. The greatest percentage of Tg IELs were detected when Ag was restricted to radioresistant cells (e.g., epithelial cells) compared with BM-derived antigenpresenting cells (APC). This was especially apparent in thymectomized chimeric mice. Consistent with the notion that Ag-bearing epithelial cells may be poor APC, isolated intestinal epithelial cells from Ag-bearing mice failed to stimulate Tg ilELs compared with splenic APC. These studies suggest that the major population of TCR γ/δ ilELs were probably extrathymically derived and encountered self-Ag on intestinal epithelial cells. The induction of tolerance likely involved an activation event resulting in downregnlation of Thy-1. These mechanisms of tolerance for TCR γ/δ ilELs led to the persistence of a reservoir of self-reactive T cells with the potential for mediating autoimmune disease.