Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg.
DC apoptosis has been observed in patients with cancer and sepsis, and defects in DC apoptosis have been implicated in the development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses, are unclear. In this study, we showed that immature viable DC have the ability to uptake apoptotic DC as well as necrotic DC without it being recognized as an inflammatory event by immature viable DC. However, the specific uptake of apoptotic DC converted immature viable DC into tolerogenic DC, which were resistant to LPS-induced maturation. These tolerogenic DC secreted increased levels of TGF-beta1, which induced differentiation of naïve T cells into Foxp3(+) Treg. Furthermore, induction of Treg differentiation only occurred upon uptake of apoptotic DC and not apoptotic splenocytes by viable DC, indicating that it is specifically the uptake of apoptotic DC that gives viable immature DC the potential to induce Foxp3(+) Treg. Taken together, these findings identify uptake of apoptotic DC by viable immature DC as an immunologically tolerogenic event.
Kushwah
Rahul
R
Physiology and Experimental Medicine Research Program, Hospital for Sick Children, Toronto, ON, Canada.
Wu
Jing
J
Oliver
Jordan R
JR
Jiang
George
G
Zhang
Jinyi
J
Siminovitch
Katherine A
KA
Hu
Jim
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D051858:Forkhead Transcription Factors / Q000032:analysis*; D007108:Immune Tolerance / Q000276:immunology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010587:Phagocytosis / Q000276:immunology*; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D053773:Transforming Growth Factor beta1; D018664:Interleukin-12; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases