CD8alpha+ dendritic cells prime TCR-peptide-reactive regulatory CD4+FOXP3- T cells.
CD4(+) T cells with immune regulatory function can be either FOXP3(+) or FOXP3(-). We have previously shown that priming of naturally occurring TCR-peptide-reactive CD4(+)FOXP3(-) Treg specifically controls Vbeta8.2(+)CD4(+) T cells mediating EAE. However, the mechanism by which these Treg are primed to recognize their cognate antigenic determinant, which is derived from the TCRVbeta8.2-chain, is not known. In this study we show that APC derived from splenocytes of naïve mice are able to stimulate cloned CD4(+) Treg in the absence of exogenous antigen, and their stimulation capacity is augmented during EAE. Among the APC populations, DC were the most efficient in stimulating the Treg. Stimulation of CD4(+) Treg was dependent upon processing and presentation of TCR peptides from ingested Vbeta8.2TCR(+)CD4(+) T cells. Additionally, DC pulsed with TCR peptide or apoptotic Vbeta8.2(+) T cells were able to prime Treg in vivo and mediate protection from disease in a CD8-dependent fashion. These data highlight a novel mechanism for the priming of CD4(+) Treg by CD8alpha(+) DC and suggest a pathway that can be exploited to prime antigen-specific regulation of T-cell-mediated inflammatory disease.
Smith
Trevor R F
TR
Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA, USA.
Maricic
Igor
I
Ria
Francesco
F
Schneider
Susan
S
Kumar
Vipin
V
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D017209:Apoptosis; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002999:Clone Cells; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007114:Immunization; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000008:administration & dosage; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D015704:CD4 Antigens; D016827:CD8 Antigens; C431698:CD8alpha antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C075784:T cell receptor Vbeta8
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