Apoptosis Threshold Set by Noxa and Mcl-1 after T Cell Activation Regulates Competitive Selection of High-Affinity Clones

作者：Wensveen Felix M; van Gi**ergen Klaas P J M; Derks Ingrid A M; Gerlach Carmen; Schumacher Ton N; van Lier Rene A W; Eldering Eric^*

来源：Immunity, 2010, 32(6): 754-765.

DOI：10.1016/j.immuni.2010.06.005

The adaptive immune system generates protective T cell responses via a poorly understood selection mechanism that favors expansion of clones with optimal affinity for antigen. Here we showed that upon T cell activation, the proapoptotic molecule Noxa (encoded by Pmaip1) and its antagonist Mcl-1 were induced. During an acute immune response against influenza or ovalbumin, Pmaip1(-/-) effector T cells displayed decreased antigen affinity and functionality. Molecular analysis of influenza-specific T cells revealed persistence of many subdominant clones in the Pmaip1(-/-) effector pool. When competing for low-affinity antigen, Pmaip1(-/-) TCR transgenic T cells had a survival advantage in vitro, resulting in increased numbers of effector cells in vivo. Mcl-1 protein stability was controlled by T cell receptor (TCR) affinity-dependent interleukin-2 signaling. These results establish a role for apoptosis early during T cell expansion, based on antigen-driven competition and survival of the fittest T cells.

• 出版日期2010-6-25