Preferential costimulation by CD80 results in IL-10-dependent TGF-beta1(+) -adaptive regulatory T cell generation.
Costimulatory ligands CD80 and CD86 have different binding preferences and affinities to their receptors, CD28 and CTLA-4. Earlier, we demonstrated that CD80 binds to CTLA-4 with higher affinity and has a role in suppressing T cell response. The current study demonstrates that not only did blockade of CD86 upon Ag presentation by bone marrow-derived dendritic cells (DC) to OVA-specific T cells result in induction of hyporesponsive T cells but also that these T cells could suppress the proliferative response of effector T cells. These T cells showed TGF-beta1 on their surface and secreted TGF-beta1 and IL-10 upon restimulation. Although blockade of CTLA-4 and neutralization of IL-10 profoundly inhibited the induction of these TGF-beta1(+) T cells, their ability to suppress the effector T cell proliferation was abrogated by neutralization of TGF-beta1 alone. Induction of TGF-beta1(+) and IL-10(+) T cells was found to be independent of natural CD4(+)CD25(+) regulatory T cells, demonstrating that preferential ligation of CTLA-4 by CD80 induced IL-10 production by effector T cells, which in turn promoted the secretion of TGF-beta1. Treatment of prediabetic NOD mice with islet beta cell Ag-pulsed CD86(-/-) DCs, but not CD80(-/-) DCs, resulted in the induction of TGF-beta1- and IL-10-producing cells, significant suppression of insulitis, and delay of the onset of hyperglycemia. These observations demonstrate not only that CD80 preferentially binds to CTLA-4 but also that interaction during Ag presentation can result in IL-10-dependent TGF-beta1(+) regulatory T cell induction, reinstating the potential of approaches to preferentially engage CTLA-4 through CD80 during self-Ag presentation in suppressing autoimmunity.
Perez
Nicolas
N
Department of Surgery, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
Karumuthil-Melethil
Subha
S
Li
Ruobing
R
Prabhakar
Bellur S
BS
Holterman
Mark J
MJ
Vasu
Chenthamarakshan
C
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism*; D051940:B7-2 Antigen / Q000378:metabolism; D060908:CTLA-4 Antigen; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D016753:Interleukin-10 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016212:Transforming Growth Factor beta; D016753:Interleukin-10