Differential impact of CD154 costimulation blockade on alloreactive effector and regulatory T cells in murine renal transplant recipients.
BACKGROUND
Although CD154 costimulation blockade prolongs allograft survival in multiple transplantation models, the underlying immunological mechanisms remain to be elucidated.


RESULTS
We used a murine orthotopic kidney allograft (KTx) model to analyze the impact of CD154 blockade on trafficking and function of alloreactive T effector versus T regulatory cells. A single dose of MR1 Ab treatment at the time of KTx significantly improved the survival of Balb/c KTx in naïve C57BL/6 recipients (mean survival time >100 days vs. 52 days in controls; P<0.005), and improved graft histology, as evidenced by decreased lymphocyte infiltration and preservation of tissue architecture (days 6-8). In the early posttransplant phase, fluorescence-activated cell sorting analysis revealed preferential depression of T effector (CD8+CD25+) and relative enrichment of T-regulatory (CD4+ CD25+ CD152+) cells selectively in KTx. This pattern was further supported by intragraft gene expression analysis, which showed increased FoxP3/Tbet ratio and simultaneously decreased granzyme B/IFN-gamma levels in Ab-treated recipients. Additionally, MR1 Ab selectively up-regulated intragraft CCL17, but suppressed CXCL9/CCL5, in parallel with increased CCR4/CCR8 but unaltered CXCR3 expression.


CONCLUSIONS
These results provide evidence, at both cellular and molecular levels, that CD154 blockade in murine KTx recipients differentially targeted T-effector and T-regulatory cell subsets by regulating intragraft induction of chemokines targeting distinct T-cell subsets.
Meng
Lingzhong
L
Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-UCLA Transplant Center, Los Angeles, CA 90095, USA.
Wu
Zheng
Z
Wang
Yue
Y
Lassman
Charles
C
Busuttil
Ronald W
RW
Zhai
Yuan
Y
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics; D015704:CD4 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors*; D060908:CTLA-4 Antigen; D017931:DNA Primers; D005434:Flow Cytometry; D006085:Graft Survival; D007371:Interferon-gamma / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
D015703:Antigens, CD; D017252:CD3 Complex; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D017931:DNA Primers; D053645:Interleukin-2 Receptor alpha Subunit; D023201:CD40 Ligand; D007371:Interferon-gamma