During development in the thymus, T cells with T cell receptors (TCRs) that bind major histocompatibility complex (MHC)-self peptide complexes with low affinity (which recognize foreign antigens) survive, and T cells with TCRs that bind MHC-self peptide complexes with high affinity (which recognize self-antigens) are eliminated. The survival pathways activated by low-affinity binding depend on activation of extracellular signal-regulated kinase (ERK), whereas the early steps through which high-affinity binding leads to apoptosis during "negative selection" are less well understood (see Palmer). McCarty et al. performed serial analysis of genes expressed in developing mouse thymocytes and found that expression of the misshapen-Nck-interacting kinase (NIK)-related kinase (MINK, a MAPKKKK) increased early in thymocyte development and then decreased after selection took place. Mice in which thymocyte MINK was knocked down through RNA interference showed increased numbers of postselection thymocytes; moreover, the deletion of autoreactive thymocytes was impaired. Western analysis combined with immunoprecipitation indicated that TCR activation in vitro promoted the association of MINK with Nck and CD3ϵ; moreover, MINK transfection or T cell activation in MINK-containing thymocytes promoted JNK (c-Jun N-terminal kinase) activation (which has been associated with TCR-dependent apoptosis). Similarly, administration of a negative selection peptide ligand in vivo promoted association of MINK, Nck, and CD3ϵ, whereas MINK was required for activation of JNK and an increase in the concentration of the proapoptotic BimEL downstream of the TCR. Thus, MINK appears to play a critical role in connecting TCR activation to apoptotic pathways in negative selection.
N. McCarty, S. Paust, K. Ikizawa, I. Dan, X. Li, H. Cantor, Signaling by the MINK is essential in the negative selection of autoreactive thymocytes. Nat. Immunol. 6, 65-72 (2005). [PubMed]
E. Palmer, Signaling negative selection: Is MINK the missing link? Nat. Immunol. 6, 9-10 (2005). [PubMed]