Dendritic cells in human thymus and periphery display a proinsulin epitope in a transcription-dependent, capture-independent fashion.
The natural expression of tissue-specific genes in the thymus, e.g., insulin, is critical for self-tolerance. The transcription of tissue-specific genes is ascribed to peripheral Ag-expressing (PAE) cells, which discordant studies identified as thymic epithelial cells (TEC) or CD11c+ dendritic cells (DC). We hypothesized that, consistent with APC function, PAE-DC should constitutively display multiple self-epitopes on their surface. If recognized by Abs, such epitopes could help identify PAE cells to further define their distribution, nature, and function. We report that selected Abs reacted with self-epitopes, including a proinsulin epitope, on the surface of CD11c+ cells. We find that Proins+ CD11c+ PAE cells exist in human thymus, spleen, and also circulate in blood. Human thymic Proins+ cells appear as mature DC but express CD8alpha, CD20, CD123, and CD14; peripheral Proins+ cells appear as immature DC. However, DC derived in vitro from human peripheral blood monocytes include Proins+ cells that uniquely differentiate and mature into thymic-like PAE-DC. Critically, we demonstrate that human Proins+ CD11c+ cells transcribe the insulin gene in thymus, spleen, and blood. Likewise, we show that mouse thymic and peripheral CD11c+ cells transcribe the insulin gene and display the proinsulin epitope; moreover, by using knockout mice, we show that the display of this epitope depends upon insulin gene transcription and is independent of Ag capturing. Thus, we propose that PAE cells include functionally distinct DC displaying self-epitopes through a novel, transcription-dependent mechanism. These cells might play a role in promoting self-tolerance, not only in the thymus but also in the periphery.
Garcia
Carlos A
CA
Immunogenetics Program and Cell Transplant Center, Diabetes Research Institute, Miller School of Medicine, University of Miami, FL 33136, USA.
Prabakar
Kamalaveni R
KR
Diez
Juan
J
Cao
Zhu Alexander
ZA
Allende
Gloria
G
Zeller
Markus
M
Dogra
Rajpreet
R
Mendez
Armando
A
Rosenkranz
Eliot
E
Dahl
Ulf
U
Ricordi
Camillo
C
Hanahan
Douglas
D
Pugliese
Alberto
A
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001324:Autoantigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D002096:C-Peptide / Q000032:analysis / Q000097:blood; D039521:CD11c Antigen / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D000939:Epitopes / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000235:genetics; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009113:Muramidase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D011384:Proinsulin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000276:immunology
D001324:Autoantigens; D002096:C-Peptide; D039521:CD11c Antigen; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D007328:Insulin; D011384:Proinsulin; C421864:hen egg lysozyme; D009113:Muramidase