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 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-gamma-producing CD8+ T cells, and inability of CD8+ T cells to transfer CS in RAG20/0 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.
Desvignes
C
C
Institut National de la Santé et de la Recherche Médicale Unité 404, Lyon, France.
Etchart
N
N
Kehren
J
J
Akiba
I
I
Nicolas
J F
JF
Kaiserlian
D
D
D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004139:Dinitrofluorobenzene / Q000008:administration & dosage / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006241:Haptens / Q000008:administration & dosage* / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010081:Oxazolone / Q000008:administration & dosage / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D019895:Transposases / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D006241:Haptens; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D010081:Oxazolone; D007371:Interferon-gamma; D004139:Dinitrofluorobenzene; D019895:Transposases