Induction of autoimmunity by expansion of autoreactive CD4+CD62Llow cells in vivo.
The prerequisites of peripheral activation of self-specific CD4(+) T cells that determine the development of autoimmunity are incompletely understood. SJL mice immunized with myelin proteolipid protein (PLP) 139-151 developed experimental autoimmune encephalomyelitis (EAE) when pertussis toxin (PT) was injected at the time of immunization but not when injected 6 days later, indicating that PT-induced alterations of the peripheral immune response lead to the development of autoimmunity. Further analysis using IA(s)/PLP(139-151) tetramers revealed that PT did not change effector T cell activation or regulatory T cell numbers but enhanced IFN-gamma production by self-specific CD4(+) T cells. In addition, PT promoted the generation of CD4(+)CD62L(low) effector T cells in vivo. Upon adoptive transfer, these cells were more potent than CD4(+)CD62L(high) cells in inducing autoimmunity in recipient mice. The generation of this population was paralleled by higher expression of the costimulatory molecules CD80, CD86, and B7-DC, but not B7-RP, PD-1, and B7-H1 on CD11c(+)CD4(+) dendritic cells whereas CD11c(+)CD8alpha(+) dendritic cells were not altered. Collectively, these data demonstrate the induction of autoimmunity by specific in vivo expansion of CD4(+)CD62L(low) cells and indicate that CD4(+)CD62L(low) effector T cells and CD11c(+)CD4(+) dendritic cells may be attractive targets for immune interventions to treat autoimmune diseases.
Amend
Bastian
B
Hertie Institute for Clinical Brain Research, Department of General Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany.
Doster
Hong
H
Lange
Christian
C
Dubois
Evelyn
E
Kalbacher
Hubert
H
Melms
Arthur
A
Bischof
Felix
F
D000276:Adjuvants, Immunologic; D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005434:Flow Cytometry; D007108:Immune Tolerance; D019041:L-Selectin / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D037342:Pertussis Toxin / Q000276:immunology; D061027:Programmed Cell Death 1 Ligand 2 Protein
D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D039521:CD11c Antigen; D018991:Myelin Proteolipid Protein; C556978:Pdcd1lg2 protein, mouse; D010446:Peptide Fragments; D061027:Programmed Cell Death 1 Ligand 2 Protein; C435023:myelin proteolipid protein (139-151); D019041:L-Selectin; D037342:Pertussis Toxin