Different mechanisms regulate CD4(+) T cell independent induction of oral and nasal tolerance of CD8(+) T cells.

Mucosal administration of antigens is known to induce antigen specific regulatory CD4+ T cells, but less is known about the effects on CD8+ T cell function. Using a murine model for mucosal tolerance induction, we show that both oral and nasal OVA (ovalbumin) application reduced OVA specific CD8+ T effector cell numbers and suppressed in vivo cytotoxicity in response to subsequent immunisation. To investigate whether CD4+ T cells are essential for oral or nasal CD8+ T cell tolerance, we used MHC class II deficient mice. Normal CD8+ T cell tolerance was observed in MHC class II deficient mice, indicating that CD4+ T cells are not required for both oral and nasal CD8+ T cell tolerance induction. To study the direct effects of mucosal antigen application on naive CD8+ T cells, we adoptively transferred OVA specific transgenic CD8+ T cells and analysed their fate after mucosal antigen application. Oral OVA application reduced the numbers of OVA specific CD8+ T cells, whereas nasal OVA application induced proliferation. However, the expanded population of OVA specific CD8+ T cells from nasally treated mice was unable to proliferate upon re-stimulation. In conclusion, our studies point to suppressive effects of the mucosal immune system directly on CD8+ T cells and indicate multiple mechanisms of tolerance induction. More insight in these mechanisms of tolerance induction is necessary for the development of mucosal tolerance therapies for autoimmune diseases and allergy.