Tolerizing effects of co-stimulation blockade rest on functional dominance of CD4+CD25+ regulatory T cells.
BACKGROUND
Clinical tolerance is the net result of regulatory and effector functions. In this article, the authors show that tolerance induction by co-stimulation blockade preferentially works through CD4CD25 regulatory T-cell-mediated suppression that is effectively achieved by selective reduction of the effector T-cell load. Anti-CD86 and anti-CD40L monoclonal antibody treatment during in vitro mixed lymphocyte reaction (MLR) typically results in the induction of a suppressive polyclonal T-cell population. This induced suppressive capacity was found to be dependent on the presence of CD4CD25 T cells at the start of MLR.


METHODS
Using a CFSE-based strategy, the authors show that within the polyclonal T-cell population, the suppressive effect was exerted by a nondividing CD4CD25 T-cell subset.


RESULTS
The cells exclusively originated from preexisting CD4CD25 regulatory T cells and proved anergic and highly suppressive on isolation. They carried the CD45RB and CD62L phenotype and expressed GITR. There was no indication of de novo induction of regulatory T cells by co-stimulation blockers. Instead, the authors observed, both in vitro and in vivo, that co-stimulation blockade shifted the ratio between alloreactive effectors and regulatory T cells in favor of the latter.


CONCLUSIONS
The authors therefore conclude that co-stimulation blockade contributes to functional dominance of regulatory T cells by preventing expansion of alloreactive effector T cells. Tolerance-inducing protocols should ideally facilitate this phenomenon.
Coenen
Jeroen J A
JJ
Department of Bloodtransfusion and Transplantation Immunology (ABTI/OV603), University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands.
Koenen
Hans J P M
HJ
van Rijssen
Esther
E
Hilbrands
Luuk B
LB
Joosten
Irma
I
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D005434:Flow Cytometry; D016027:Heart Transplantation / Q000276:immunology*; D007165:Immunosuppression Therapy; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D015704:CD4 Antigens; D015375:Receptors, Interleukin-2