Lymphotoxin controls α_Eβ7‐integrin expression by peripheral CD8⁺ T cells

Abstract

Lymphotoxin (LT)‐α, a member of the TNF family, is recognized as an important mediator in different aspects of lymphoid organ development. Targeted disruption of this molecule resulted in a substantial reduction in the proportion of αEβ7‐integrinhigh CD8+ T cells detectable in peripheral lymphoid organs. This defect, however, was not observed on mature CD4–CD8+ thymocytes. To determine whether this was due to downregulation of β7‐integrin expression by peripheral CD8+ T cells or a failure of thymic emigration of CD8+ β7‐integrinhigh T cells, β7‐integrin was examined on recent thymic emigrants (RTE). When analysed within 16 h after leaving the thymus CD4–CD8+ RTE in both LT‐α–/– and wild type (wt) mice remained β7‐integrinhigh and were indistinguishable. However, within 3–5 days, emigration loss of β7‐integrin became evident in LT‐α–/– mice. Despite this loss, the proportion of thymically derived αβTCR+ T‐cell populations in the intestinal epithelium, an important target tissue of CD8+ αEβ7‐integrinhigh T cells, was increased in the absence of LT‐α. In contrast, B cells were detectable only rarely in the intestinal tissue of LT‐α–/– mice. The expression of E‐Cadherin remained unchanged. These results indicate that a LT‐α‐dependent process maintains a high level of αEβ7‐integrin expression by peripheral CD8+ T cells, and with this control mechanism LT‐α may help to regulate CD8+ T‐cell numbers in the tissues.

A unique lymphotoxin αβ-dependent pathway regulates thymic emigration of Vα14 invariant natural killer T cells

“…By contrast, thymic emigration of conventional T cells was not decreased in LT␤R 0/0 mice and was even slightly enhanced in LT␣ 0/0 mice. These findings corroborate earlier reports in which recently emigrated splenic CD8 ϩ T cell numbers were found to be increased in LT␣ 0/0 mice versus controls (36). Our data strongly support a model in which an LT␤R-expressing thymic stromal cell type controls the emigration of V␣14i NKT cells from the thymus to the peripheral organs.…”

Inhibition of the lymphotoxin pathway as a therapy for autoimmune disease

“…For example, CCL20 was noted to be under LT control in one setting (78). LTbR-Ig administration to adult mice decreased the numbers of aEb7 1 CD8 cells in the blood (unpublished data), mimicking the decrease noted in LTa-and LTbR-deficient mice (153,154). As noted above, the DC content of colonic patches in the inflamed gut was reduced by LTbR-Ig administration, yet currently this observation remains undeveloped, despite the potentially powerful consequences (58).…”

T cell abnormalities in systemic lupus erythematosus

“…Indeed, the interaction between aEb7 and E-cadherin has been demonstrated to induce apoptosis in glandular epithelial cells in Sjogren's syndrome [15], indicating that apoptosis triggered by these adhesion molecules may be a novel and unique mechanism to explain the tissue injury in SLE ( Figure 1). aEb7 is not expressed in resting peripheral blood lymphocytes (PBL), but its expression can be induced by IL-4, TGF-b, and lymphotoxin [16,17]. CD8 þ intra-epithelial lymphocytes in the gut express this integrin without further activation [18].…”