High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance.
BACKGROUND
Both dendritic cells (DC) and T-regulatory cells (Treg) have been implicated in regulation of alloimmune responses and transplant tolerance.


METHODS
We analyzed B7 coregulatory molecule expression on circulating DC subset precursors, together with CD4+CD25(hi) Foxp3+ Treg by rare event, flow cytometric analysis in operationally tolerant pediatric liver transplant recipients (TOL), those undergoing prospective immunosuppressive drug weaning (PW) or maintenance immunosuppression (MI), and normal healthy individuals (controls).


RESULTS
Use of DC subset-specific monoclonal antibodies confirmed elevated precursor plasmacytoid DC/myeloid DC ratios in TOL and PW compared with MI. In addition, Treg frequencies were higher in TOL than in PW and MI, but not controls. While there was no difference in levels of costimulatory and coinhibitory molecules on precursor myeloid DC between the groups, the programmed death ligand-1 (PD-L1=B7-H1):CD86 (B7-2) ratio on precursor plasmacytoid DC was significantly higher in TOL than MI and correlated with the Treg frequency. There was no relation between prednisone or tacrolimus dose or tacrolimus trough level and either the PD-L1/CD86 ratio on plasmacytoid DC or the Treg frequency. Moreover, clinically relevant concentrations of dexamethasone or tacrolimus did not affect these values in short-term culture.


CONCLUSIONS
These novel findings suggest a possible functional relationship between the enhanced incidence of precursor plasmacytoid DC, their comparatively high relative expression of the coinhibitory molecule PD-L1, and the elevated frequency of Treg in operational liver transplant tolerance.
Tokita
Daisuke
D
Thomas E. Starzl Transplantation Institute and the Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Mazariegos
George V
GV
Zahorchak
Alan F
AF
Chien
Nydia
N
Abe
Masanori
M
Raimondi
Giorgio
G
Thomson
Angus W
AW
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000097:blood / Q000276:immunology*; D051940:B7-2 Antigen / Q000097:blood / Q000276:immunology*; D060890:B7-H1 Antigen; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007223:Infant; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D011241:Prednisone; D016559:Tacrolimus