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Induction of Eye-Derived Tolerance Does Not Depend on Naturally Occurring CD4⁺CD25⁺ T Regulatory Cells

¹From the Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts; the ³Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan; and the ⁴Laboratory of Experimental Pathology, Aichi Cancer Institute, Nagoya, Japan.

PURPOSE. Regulatory CD4⁺ T cells (T regs) arise in the spleens of mice with anterior chamber–associated immune deviation (ACAID), an eye-derived tolerance evoked by injection of antigen into the ocular anterior chamber (AC). The current study was conducted to investigate the possibility that these T regs express CD25 and are derived from natural CD4⁺CD25⁺ T cells.

METHODS. Naïve T cells from DO11.10 mice were activated in vitro by ovalbumin (OVA)-pulsed, TGFß-treated antigen-presenting cells (APCs), and the expression of CD25 assayed by flow cytometry. OVA-specific ACAID T regs were obtained from the spleens of DO11.10 mice with ACAID to OVA. Immunomagnetic enrichment was used to sort out CD4⁺CD25⁺, and CD4⁺CD25^– ACAID T cells before they were injected into OVA-immunized mice or examined for mRNA expression of the regulatory T-cell transcription factor Foxp3. In addition, before AC injection of OVA, systemic depletion of CD25⁺ T cells was performed with injections of anti-IL-2 receptor antibody into the mice.

RESULTS. OVA-specific T cells from DO11.10 mice expressed CD25 when exposed to OVA-pulsed, TGFß-treated APCs, even when the DO11.10 T cells were depleted of CD25⁺ cells before their in vitro stimulation. In addition, DH was suppressed in naïve mice that were injected with CD4⁺CD25⁺ or CD4⁺CD25^– ACAID T cells. The CD4⁺CD25⁺, but not the CD4⁺CD25^–, ACAID T regs expressed Foxp3. Finally, OVA induced ACAID in mice depleted of CD25⁺ cells.

CONCLUSIONS. Some of the CD4⁺ T regs of ACAID arise from CD25^– precursors, and the induction of ACAID is not dependent on the presence of natural CD4⁺CD25⁺ T regs.

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