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In Vitro Generation of Regulatory CD8⁺ T Cells Similar to those Found in Mice with Anterior Chamber–Associated Immune Deviation

From the Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.

PURPOSE. When injected intravenously into naïve mice, peritoneal exudate cells (PECs) incubated with ovalbumin (OVA) in the presence of transforming growth factor (TGF)-ß2 induce immune deviation similar to that evoked by injection of OVA into the anterior chamber of the eye. Intraocular antigen injection elicits two distinct populations of regulatory T cells that impair delayed hypersensitivity (DH) by two different mechanisms: a CD4⁺ T cell that suppresses the induction of DH (afferent) and a CD8⁺ T cell that inhibits DH expression. In an effort to understand the origin and mechanism of action of these regulatory cells, CD8⁺ T cells from OVA-specific T cell receptor (Tcr) transgenic mice (OT-1) were used.

METHODS. CD8⁺ T cells were harvested from Tcr transgenic OT-I mice whose Tcr recognize an OVA peptide in the context of the class I major histocompatibility complex molecule K^b. These cells were stimulated in vitro with OVA-pulsed PECs exposed (or not) to TGF-ß2, then analyzed for their capacity to proliferate, to secrete various cytokines, to lyse OVA-expressing target cells, and to regulate bystander T cells in vitro and in vivo.

RESULTS. When OVA-pulsed PECs were used in vitro as stimulators, responding OT-I T cells proliferated and preferentially secreted interferon (IFN)-, interleukin (IL)-2, and tumor necrosis factor (TNF)-, rather than IL-4 and IL-10. When the stimulator PECs were pretreated with TGF-ß2 and then pulsed with OVA, responding OT-I T cells proliferated even more swiftly, but they secreted significantly less IFN-, IL-2, and TNF-, and no IL-4 or IL-10. OT-I T cells, which constitutively display cytotoxicity toward OVA-expressing target cells, lost this activity when stimulated with OVA-pulsed, TGF-ß2–pretreated PECs. Moreover, OT-I T cells stimulated in this manner displayed the capacity to inhibit proliferation of OVA-primed T cells exposed to OVA in vitro and to suppress in vivo the expression of OVA-triggered DH.

CONCLUSIONS. OVA-pulsed PECs, pretreated with TGF-ß2, coerce naïve OVA-specific CD8⁺ T cells to become efferent regulators of DH similar to the regulatory T cells evoked by intraocular injection of OVA.

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