CMS links the tail

Pre–T-cell receptor (TCR) triggers a number of signals that are crucial for sustaining the complex differentiation program of T lymphocytes. Research has shown that pre-TCR signaling is required for the induction of proliferation, TCRβ allelic exclusion, and transition from CD4^–CD8^– to CD4⁺CD8⁺ thymocytes.¹  In order to signal, TCRs need to be recruited to the cell surface; unlike αβ and γδTCR, pre-TCR localizes cells autonomously to membrane rafts of thymocytes, and its signaling is constitutive and ligand independent. Moreover, analysis of the function of different structural domains of pTα, carried out by overexpressing pTα mutant transgenes in pTα^–/– mice, has demonstrated that a proline-rich motif included in the cytoplasmic tail of pTα is required for the function of pre-TCR.²  However, the adaptor protein(s) interacting with and allowing the constitutive targeting of pTα/pre-TCR to the membrane rafts have so far remained unidentified.

Navarro and colleagues now suggest that the polyproline-arginine sequence in the human pTα cytoplasmic tail interacts in vitro with SH3 domains of the CIN85/CMS family of adaptors and, notably, that only one of those adaptors, CMS, interacts in vivo with human pTα. In support of this interaction's physiologic relevance, the authors found that deletion of the pTα CIN85/CMS-binding motif impairs pre-TCR mediated Ca²⁺ mobilization and NFAT transcriptional activity. The authors therefore suggest that CMS may act as a scaffolding molecule and be required for propagation of pre-TCR signaling.

Pre-TCR signaling also controls pTα transcription, and we know that pre-TCR function should be shut down to allow full function of αβTCR.³  To this end, pre-TCR signaling may result in the arrest of pTα and the triggering of TCRα transcription. This, together with the higher pairing efficiency of TCRβ with TCRα rather than with pTα, may finally favor the switch from pre-TCR to the αβTCR expression, thus sustaining differentiation progression. Besides the arrest of pTα transcription, which certainly leads to decreased pre-TCR expression, attenuation of pre-TCR expression and function may also be due to induced/increased pTα degradation. Navarro et al show that the CMS C-terminus is able to associate with polymerized actin in the endocytic compartment, colocalizing with internalized pTα in its trafficking to lysosomes. Moreover, the observation that CMS is up-regulated in post-β selected CD4⁺CD8⁺ thymocytes further supports a physiological role for CMS in attenuating pre-TCR signaling.

Overall, the data from Navarro and colleagues seem to suggest that CMS represents a pivotal regulator of pre-TCR function, being able, via its SH3 domains, to link the cytoplasmic tail of pTα and favor amplification of pre-TCR signaling and, through its C-terminal region, to allow pTα degradation, thus driving signaling attenuation. Given the increasing evidence of the crucial role deregulated pre-TCR signaling plays in sustaining a number of oncogenic pathways involved in T-cell leukemogenesis, the identification of molecules directly involved in regulating the balance between activation and degradation of pre-TCR may help to design novel therapeutic strategies.