Cd1-Reactive Natural Killer T Cells Are Required for Development of Systemic Tolerance through an Immune-Privileged Site

TLDR

Systemic tolerance can be induced by antigen introduction into immune‑privileged sites such as the eye, a process exemplified by ACAID, but this tolerance fails in mouse strains lacking natural killer T cells. The study aimed to determine whether CD1‑reactive NKT cells are essential for eye‑induced systemic tolerance and to explore their potential role in self‑tolerance and autoimmunity. CD1‑reactive NKT cells are required for eye‑induced ACAID, as shown by failure of CD1‑knockout mice, NKT cell depletion, and anti‑CD1 treatment to develop tolerance, whereas intravenous tolerance develops independently of NKT cells.

Abstract

Systemic tolerance can be elicited by introducing antigen into an immune-privileged site, such as the eye, or directly into the blood. Both routes of immunization result in a selective deficiency of systemic delayed type hypersensitivity. Although the experimental animal model of anterior chamber–associated immune deviation (ACAID) occurs in most mouse strains, ACAID cannot be induced in several mutant mouse strains that are coincidentally deficient in natural killer T (NKT) cells. Therefore, this model for immune-privileged site–mediated tolerance provided us with an excellent format for studying the role of NKT cells in the development of tolerance. The following data show that CD1-reactive NKT cells are required for the development of systemic tolerance induced via the eye as follows: (a) CD1 knockout mice were unable to develop ACAID unless they were reconstituted with NKT cells together with CD1+ antigen-presenting cells; (b) specific antibody depletion of NKT cells in vivo abrogated the development of ACAID; and (c) anti-CD1 monoclonal antibody treatment of wild-type mice prevented ACAID development. Significantly, CD1-reactive NKT cells were not required for intravenously induced systemic tolerance, thereby establishing that different mechanisms mediate development of tolerance to antigens inoculated by these routes. A critical role for NKT cells in the development of systemic tolerance associated with an immune-privileged site suggests a mechanism involving NKT cells in self-tolerance and their defects in autoimmunity.