The thymus plays a role in oral tolerance in experimental autoimmune encephalomyelitis.
The oral administration of myelin proteins has been used for the successful prevention and treatment of experimental autoimmune encephalomyelitis (EAE). We questioned whether the thymus was involved in oral tolerance. In this study, euthymic myelin basic protein (MBP) TCR transgenic mice are protected from EAE when fed MBP but are not protected when thymectomized. Similarly, in a cell transfer system, T cell responses to OVA measured in vivo were suppressed significantly only in the OVA-fed euthymic mice but not in the thymectomized mice. We observed that the absence of the thymus dramatically enhanced the Th1 response. We explored three alternatives to determine the role of the thymus in oral tolerance: 1) as a site for the induction of regulatory T cells; 2) a site for deletion of autoreactive T cells; or 3) a site for the dissemination of naive T cells. We found that Foxp3(+)CD4(+)CD25(+) T cells are increased in the periphery but not in the thymus after Ag feeding. These CD4(+)CD25(+) T cells also express glucocorticoid-induced TNFR and intracellular CTLA4 and suppress Ag-specific proliferation of CD4(+)CD25(-) cells in vitro. The thymus also plays a role in deletion of autoreactive T cells in the periphery following orally administered MBP. However, thymectomy does not result in homeostatic proliferation and the generation of memory cells in this system. Overall, the oral administration of MBP has a profound effect on systemic immune responses, mediated largely by the generation of regulatory T cells that act to prevent or suppress EAE.
Song
Fei
F
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA. song.89@osu.edu
Guan
Zhen
Z
Gienapp
Ingrid E
IE
Shawler
Todd
T
Benson
Jacqueline
J
Whitacre
Caroline C
CC
D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation; D017637:Clonal Deletion / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D018928:Immunity, Mucosal / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009061:Mouth Mucosa / Q000276:immunology*; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013934:Thymectomy; D013950:Thymus Gland / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D004676:Myelin Basic Protein; D015375:Receptors, Interleukin-2