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Oral Administration of Hapten Inhibits In Vivo Induction of Specific Cytotoxic CD8⁺ T Cells Mediating Tissue Inflammation: A Role for Regulatory CD4⁺ T Cells¹

Cyril Desvignes^*, Nathalie Etchart^*, Jeanne Kehren, Itoshi Akiba, Jean-François Nicolas and Dominique Kaiserlian^2,*

^* Institut National de la Santé et de la Recherche Médicale Unité 404, Lyon, France; and Institut National de la Santé et de la Recherche Médicale Unité 503, Immunodermatology, Faculté Laennec, Lyon, France

We investigated whether oral tolerance could block the development of an inflammatory response mediated by CD8⁺ T cells, using a mouse model of oral tolerance of contact sensitivity (CS) to the hapten 2,4-dinitrofluorobenzene (DNFB). In this system, the skin inflammatory response is initiated by hapten-specific class I-restricted cytotoxic CD8⁺ T (CTL) cells, independently of CD4 help. Oral delivery of DNFB before skin sensitization blocked the CS response by impairing the development of DNFB-specific CD8⁺ effector T cells in secondary lymphoid organs. This was shown by complete inhibition of DNFB-specific CTL and proliferative responses of CD8⁺ T cells, lack of specific IFN--producing CD8⁺ T cells, and inability of CD8⁺ T cells to transfer CS in RAG2^0/0 mice. RT-PCR and immunohistochemical analysis confirmed that recruitment of CD8⁺ effectors of CS in the skin at the site of hapten challenge was impaired in orally tolerized mice. Sequential anti-CD4 Ab treatment showed that only depletion of CD4⁺ T cells during the afferent phase of CS abrogated oral tolerance induction by restoring high numbers of specific CD8⁺ effectors in lymphoid organs, whereas CD4 depletion during the efferent phase of CS did not affect oral tolerance. These data demonstrate that a single intragastric administration of hapten can block in vivo induction of DNFB-specific CD8⁺ CTL responsible for tissue inflammation and that a subset of regulatory CD4⁺ T cells mediate oral tolerance by inhibiting expansion of specific CD8⁺ effectors in lymph nodes.

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