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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4140-4141.
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IMMUNOBIOLOGY
Comment on Navarro et al, page 4331
CMS links the tail
Isabella Screpanti
SAPIENZA UNIVERSITY OF ROME
In this issue of Blood, Navarro and colleagues report the first molecular evidence for a pT intracellular adaptor involved in human pre-TCR (T-cell receptor) function.
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 β and   TCR, 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 pT, carried out by overexpressing pT mutant transgenes in pT–/– mice, has demonstrated that a proline-rich motif included in the cytoplasmic tail of pT is required for the function of pre-TCR.2 However, the adaptor protein(s) interacting with and allowing the constitutive targeting of pT/pre-TCR to the membrane rafts have so far remained unidentified.
Navarro and colleagues now suggest that the polyproline-arginine sequence in the human pT 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 pT. In support of this interaction's physiologic relevance, the authors found that deletion of the pT 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 pT transcription, and we know that pre-TCR function should be shut down to allow full function of βTCR.3 To this end, pre-TCR signaling may result in the arrest of pT and the triggering of TCR transcription. This, together with the higher pairing efficiency of TCRβ with TCR rather than with pT, may finally favor the switch from pre-TCR to the βTCR expression, thus sustaining differentiation progression. Besides the arrest of pT transcription, which certainly leads to decreased pre-TCR expression, attenuation of pre-TCR expression and function may also be due to induced/increased pT degradation. Navarro et al show that the CMS C-terminus is able to associate with polymerized actin in the endocytic compartment, colocalizing with internalized pT 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 pT and favor amplification of pre-TCR signaling and, through its C-terminal region, to allow pT 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.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- von Boehmer H. Unique features of the pre-T-cell receptor -chain: not just a surrogate. Nat Rev Immunol 2005; 5:571–577.[CrossRef][Medline]
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- Aifantis I, Borowski C, Gounari F, Lacorazza HD, Nikoloch-Zugich J, von Boehmer H. A critical role for the cytoplasmic tail of pT in T lymphocyte development. Nat Immunol 2002; 3:483–488.[Medline]
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- Yamasaki S and Saito T. Molecular basis for pre-TCR-mediated autonomous signaling. Trends Immunol 2007; 28:39–43.[CrossRef][Medline]
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Related Article in Blood Online:
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Identification of CMS as a cytosolic adaptor of the human pT chain involved in pre-TCR function
- María N. Navarro, Gretel Nusspaumer, Patricia Fuentes, Sara González-García, Juan Alcain, and María L. Toribio
Blood 2007 110: 4331-4340.
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