CD4⁺ NKT cells, but not conventional CD4⁺ T cells, are required to generate efferent CD8⁺ T regulatory cells following antigen inoculation in an immune-privileged site

Following inoculation of Ag into the anterior chamber (a.c.), systemic tolerance develops that is mediated in part by Ag-specific efferent CD8⁺ T regulatory (Tr) cells. This model of tolerance is called a.c.-associated immune deviation. The generation of the efferent CD8⁺ Tr cell in a.c.-associated immune deviation is dependent on IL-10-producing, CD1d-restricted, invariant Vα14⁺ NKT (iNKT) cells. The iNKT cell subpopulations are either CD4⁺ or CD4^-CD8^- double negative. This report identifies the subpopulation of iNKT cells that is important for induction of the efferent Tr cell. Because MHC class II^-/- (class II^-/-) mice generate efferent Tr cells following a.c. inoculation, we conclude that conventional CD4⁺, T cells are not needed for the development of efferent CD8⁺ T cells. Furthermore, Ab depletion of CD4⁺ cells in both wild-type mice (remove both conventional and CD4⁺ NKT cells) and class II^-/- mice (remove CD4⁺ NKT cells) abrogated the generation of Tr cells. We conclude that CD4⁺ NKT cells, but not the class II molecule or conventional CD4⁺ T cells, are required for generation of efferent CD8⁺ Tr cells following Ag introduction into the eye. Understanding the mechanisms that lead to the generation of efferent CD8⁺ Tr cells may lead to novel immunotherapy for immune inflammatory diseases.