Oral administration of hapten inhibits in vivo induction of specific cytotoxic CD8+ T cells mediating tissue inflammation: A role for regulatory CD4+T cells

We investigated whether oral tolerance could block the development of an in flammatory response mediated by CD8(+) T cells, using a mouse model of oral tolerance of contact sensitivity (CS) to the hapten 2,4-dinitrofluorobenze ne (DNFB), In this system, the skin inflammatory response is initiated by h apten-specific class I-restricted cytotoxic CD8(+) T (CTL) cells, independe ntly of CD4 help. Oral delivery of DNFB before skin sensitization blocked t he CS response by impairing the development of DNFB-specific CD8(+) effecto r T cells in secondary lymphoid organs. This was shown by complete inhibiti on of DNFB-specific CTL and proliferative responses of CD8(+) T cells, lack of specific IFN-gamma-producing CD8(+) T cells, and inability of CD8(+) T cells to transfer CS in RAG2(0/0) mice. RT-PCR and immunohistochemical anal ysis confirmed that recruitment of CD8(+) effecters of CS in the skin at th e site of hapten challenge was impaired in orally tolerized mice. Sequentia l anti-CD4 Ab treatment showed that only depletion of CD4(+) T cells during the afferent phase of CS abrogated oral tolerance induction by restoring h igh numbers of specific CD8(+) effecters in lymphoid organs, whereas CD4 de pletion during the efferent phase of CS did not affect oral tolerance. Thes e 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 to lerance by inhibiting expansion of specific CD8(+) effecters in lymph nodes .