Multiple negative feedbacks on CD152 expression in allograft tolerance.
BACKGROUND
CD152 has been implicated in tolerance induction. This study investigated how CD80 and CD86 regulated CD152 expression in a low-responding cardiac transplant model with CD152-mediated long-term graft acceptance.


METHODS
A low-responding cardiac transplant model from BALB/c to B10.A was used. Donor-specific stimulation and multiple antibody blockade of the CD80/CD86:CD28/CD152 co-stimulatory pathway was applied to the splenic T cells from B10.A recipients with 100-day grafts (B10.A-100). Proliferation assays, quantitative (Q) real-time polymerase chain reaction (PCR), flow cytometric analyses, and fluorescence microscopy were conducted to examine the roles of CD80 and CD86 in CD152 expression.


RESULTS
B10.A-100 splenic T cells were hyporesponsive to donor-specific stimulation, and anti-CD80, anti-CD86, or anti-CD152 treatment significantly enhanced the proliferation response of the B10.A-100 splenic T cells. Proliferation assays and Q-PCR revealed that CD152 inhibited T-cell proliferation and, at the same time, decreased CD152 expression by secluding CD80 and CD86 from CD28 engagement. Flow cytometric analyses and fluorescence microscopy showed that CD28 engagement facilitated intracellular accumulation of CD152. Besides, CD152 engagement by CD80 decreased CD152 mRNA transcription, and CD152 engagement by CD86 inhibited surface expression of CD152.


CONCLUSIONS
CD80 and CD86 controlled CD152-mediated allograft tolerance by multiple negative feedbacks on CD152 mRNA and surface expression.
Tsai
Meng-Kun
MK
Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Chung-Shan South Road,Taipei, 100, Taiwan.
Ho
Hong-Nerng
HN
Chien
Hsiung-Fei
HF
Tzeng
Mei-Ching
MC
Chen
Chien-Hsing
CH
Lee
Po-Huang
PH
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D002455:Cell Division; D017931:DNA Primers; D005260:Female; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology / Q000528:radiation effects; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D014184:Transplantation, Homologous / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D017931:DNA Primers; D008562:Membrane Glycoproteins