GM-CSF-induced CD11c+CD8a--dendritic cells facilitate Foxp3+ and IL-10+ regulatory T cell expansion resulting in suppression of autoimmune thyroiditis.
GM-CSF plays an essential role in the differentiation of dendritic cells (DCs). Our studies have shown that GM-CSF treatment can induce semi-mature DCs and CD4+CD25+ regulatory T cells (Tregs) and suppress ongoing autoimmunity in mouse models. In this study, we examined the differences in the potential of GM-CSF to exert tolerogenic function on CD8a+ and CD8a- sub-populations of DCs in vivo. We show that GM-CSF modulates CD8a-, but not CD8a+ DCs in vivo, by inhibiting the surface expression of activation markers MHC II and CD80 and production of inflammatory cytokines such as IL-12 and IL-1beta. Self-antigen [mouse thyroglobulin (mTg)] presentation by GM-CSF-exposed CD8a- DCs to T cells from mTg-primed mice induced a profound increase in the frequency of forkhead box P3 (FoxP3)-expressing T cells compared with antigen presentation by GM-CSF-exposed CD8a+ DCs and control CD8a+ and CD8a- DCs. This tolerogenic property of GM-CD8a- DCs was abrogated when IL-12 was added. GM-CSF-exposed CD8a- DCs could also induce secretion of significantly higher amounts of IL-10 by T cells from mTg-primed mice. Importantly, adoptive transfer of CD8a- DCs from GM-CSF-treated SCID mice, but not untreated mice, into wild-type CBA/J mice prevented the development of experimental autoimmune thyroiditis (EAT) in the recipient animals upon immunization with mTg. Collectively, our results show that GM-CSF renders CD8a- DCs tolerogenic, and these DCs induce Foxp3+ and IL-10+ Tregs.
Ganesh
Balaji B
BB
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Cheatem
Donald M
DM
Sheng
Jian Rong
JR
Vasu
Chenthamarakshan
C
Prabhakar
Bellur S
BS
D000818:Animals; D017951:Antigen Presentation; D039521:CD11c Antigen; D016827:CD8 Antigens; D002454:Cell Differentiation; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism*; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D017634:Self Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D013954:Thyroglobulin / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D014611:Vaccination
D039521:CD11c Antigen; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053583:Interleukin-1beta; D016753:Interleukin-10; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013954:Thyroglobulin