{'fraction_non_alphanumeric': 0.028042959427207637, 'fraction_numerical': 0.013723150357995227, 'mean_word_length': 5.45, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
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 CD4+CD25+ 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 CD4+CD25+ 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 CD4+CD25high T-cell subset. Results. The cells exclusively originated from preexisting CD4+CD25+ regulatory T cells and proved anergic and highly suppressive on isolation. They carried the CD45RBlow and CD62Lhigh 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. Conclusion. 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.