Costimulation blockade-induced cardiac allograft tolerance: inhibition of T cell expansion and accumulation of intragraft cD4(+)Foxp3(+) T cells.
BACKGROUND
Previous studies have demonstrated that anti-CD40L or anti-B7 requires the presence of CD4(+)CD25(+) regulatory T cells (Treg) to induce antigen specific hyporesponsiveness. Other tolerance strategies involving Treg have shown a dependency on interleukin (IL)-10. The objective of this study was to investigate the role of CD4(+)CD25(+) Treg and IL-10 when treating transplant recipients with cytotoxic T lymphocyte-associated antigen (CTLA)-4 immunoglobulin (Ig), anti-CD40L, and anti-lymphocyte function-associated antigen (LFA)-1.


METHODS
Recombinase activating gene-deficient (Rag1(-/-) mice were transplanted with BALB/c hearts and adoptively transferred with IL-10(-/-) CD4(+) T cells, CD4(+)CD25(-) T cells or CD4(+)CD25(-)CD103(-) T cells and treated with costimulation blockade. Intragraft T cells from C57BL/6 recipients were analyzed for the expression of the Foxp3 protein after tolerance induction.


RESULTS
Mice reconstituted with IL-10(-/-) CD4(+) T cells, CD4(+)CD25(-) T cells or CD4(+)CD25(-) CD103(-) T cells and treated with costimulation blockade accepted allografts permanently. Analysis of cells from recipient mice adoptively transferred with CD4(+)CD25(-) T cells contained a population of CD4(low)CD25(+) T cells 100 days after transplantation. Costimulation blockade partially prevented the homeostatic proliferation of CD4(+)CD25(-)CD103(-) T cells in Rag-1(-/-) recipients. Accepted allografts contained an elevated number of CD4(+)Foxp3(+) T cells.


CONCLUSIONS
These results indicate that T-cell derived IL-10 is not essential for induction of graft acceptance in mice treated with costimulation blockade, but that treatment limits T-cell expansion in the recipients. The results further indicate that tolerance is maintained by intragraft CD4(+)Foxp3(+) T cells.
Oderup
Cecilia
C
Section for Immunology, Lund University, Lund, Sweden.
Malm
Helene
H
Ekberg
Henrik
H
Qi
Zhongquan
Z
Veress
Béla
B
Ivars
Fredrik
F
Corbascio
Matthias
M
D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000494:pharmacology*; D015704:CD4 Antigens / Q000032:analysis; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology; D060908:CTLA-4 Antigen; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000378:metabolism; D016654:Genes, RAG-1 / Q000235:genetics; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007074:Immunoglobulin G / Q000494:pharmacology*; D016753:Interleukin-10 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D023001:Transplantation Tolerance
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D016169:Lymphocyte Function-Associated Antigen-1; D016753:Interleukin-10; D023201:CD40 Ligand