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Yet, in spite of the robust nature of the tolerance\u2010inducing potential of costimulation blockade, a comprehensive understanding of the molecular and cellular mechanisms underlying tolerance induction is still missing. Nevertheless, progress has been continuously made. In this issue of the <jats:italic>European Journal of Immunology<\/jats:italic>, Chai et\u00a0al. [Eur. J. Immunol. 2015. 45: 2017\u20132027] show that transplantation tolerance induced with an anti\u2010CD154 monoclonal antibody relies on the coexistence of several tolerogenic mechanisms rather than one simple regulatory mechanism. These observations highlight the importance of concerted actions involving multiple pathways, namely apoptosis, acquisition of regulatory cells, or inhibition of proliferation, all of which contribute to the induction and maintenance of robust immune tolerance. 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