Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis.
Chronic progression of relapsing experimental autoimmune encephalomyelitis (R-EAE), a mouse model of multiple sclerosis (MS), is dependent on the activation of T cells to endogenous myelin epitopes, that is, epitope spreading. This review focuses on the cellular and molecular mechanisms underlying the process of epitope spreading. Surprisingly, activation of naïve T cells to endogenous myelin epitopes in SJL mice undergoing R-EAE occurs directly in the central nervous system (CNS), a site generally perceived to be immunologically privileged. Determination of the antigen presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with established R-EAE shows that peripherally derived CD11b(+)CD11c(+)CD45(hi) myeloid dendritic cells (mDCs) most efficiently present endogenous myelin antigens to activate both preactivated effector myelin-specific T cells and naïve T cells. The mDCs, which drive epitope spreading, preferentially polarize pathogenic Th17 responses correlating with their enhanced expression of TGF-beta1, IL-6, and IL-23. Both B220(+)CD11c(+) plasmacytoid (pDCs) and CD8alpha(+)CD11c(+) (CD8 DCs) were superior to CD11b(+)CD11c(-)CD45(hi) macrophages, but less efficient than mDCs at presenting endogenous peptide to induce Th17 cells. In contrast, CNS-resident CD11b(+)CD11c(-)CD45(low) microglia purified from the inflamed CNS were found to be largely incapable of activating either naïve or effector T cells.
Miller
Stephen D
SD
Department of Microbiology, Northwestern University Medical School, Chicago, IL 60611, USA. s-d-miller@northwestern.edu
McMahon
Eileen J
EJ
Schreiner
Bettina
B
Bailey
Samantha L
SL
D000818:Animals; D002490:Central Nervous System / Q000276:immunology*; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D018448:Models, Immunological; D009103:Multiple Sclerosis / Q000276:immunology*; D012008:Recurrence
D000939:Epitopes