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.
van den Berg
Hendrik
H
Department Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Greuter
Mascha
M
Kraal
Georg
G
den Haan
Joke M M
JM
D000284:Administration, Oral; D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D007108:Immune Tolerance; D007165:Immunosuppression Therapy / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D009061:Mouth Mucosa / Q000276:immunology*; D009297:Nasal Mucosa / Q000276:immunology*; D010047:Ovalbumin; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000941:Antigens; D010446:Peptide Fragments; D010047:Ovalbumin