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J. Biol. Chem., Vol. 282, Issue 31, 22324-22334, August 3, 2007

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Loss of N-terminal Charged Residues of Mouse CD3 Chains Generates Isoforms Modulating Antigen T Cell Receptor-mediated Signals and T Cell Receptor-CD3 Interactions^*

Raquel Bello¹, Maria Jose Feito, Gloria Ojeda, Pilar Portolés², and Jose M. Rojo³

From the Departamento de Fisiopatología Celular y Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, E-28040 Madrid, Spain and the Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain

The antigen T cell receptor (TCR)-CD3 complexes present on the cell surface of CD4⁺ T lymphocytes and T cell lines express CD3 chain isoforms with different isoelectric points (pI), with important structural and functional consequences. The pI values of the isoforms fit the predicted pI values of CD3 chains lacking one, two, and three negatively charged amino acid residues present in the N-terminal region. Different T cells have different ratios of CD3 chain isoforms. At a high pI, degraded CD3 isoforms can be better recognized by certain anti-CD3 monoclonal antibodies such as YCD3-1, the ability of which to bind to the TCR-CD3 complex is directly correlated with the pI of CD3. The abundance of CD3 isoforms can be modified by treatment of T cells with the proteinase inhibitor phenanthroline. In addition, these CD3 isoforms have functional importance. This is shown, first, by the different structure of TCR-CD3 complexes in cells possessing different amounts of isoforms (as observed in surface biotinylation experiments), by their different antigen responses, and by the stronger interaction between low pI CD3 isoforms and the TCR. Second, incubation of cells with phenanthroline diminished the proportion of degraded high pI CD3 isoforms, but also the ability of the cells to deliver early TCR activation signals. Third, cells expressing mutant CD3 chains lacking N-terminal acid residues showed facilitated recognition by antibody YCD3-1 and enhanced TCR-mediated activation. Furthermore, the binding avidity of antibody YCD3-1 was different in distinct thymus populations. These results suggest that changes in CD3 N-terminal chains might help to fine-tune the response of the TCR to its ligands in distinct activation situations or in thymus selection.

Received for publication, March 5, 2007 , and in revised form, June 6, 2007.

^* This work was supported in part by Grants ISCIII-01/30 and ISCIII-05/054 from the Ministerio de Sanidad y Consumo (Spain) and Grants BMC2001-2177 and SAF2004-06852 from the Ministerio de Ciencia y Tecnología (Spain) (to P. P. and J. M. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a fellowship from the Ministerio de Ciencia y Tecnología (Spain).

² Tenured scientist of the Consejo Superior de Investigaciones Científicas at the Centro Nacional de Microbiología, Instituto de Salud Carlos III.

³ To whom correspondence should be addressed: Dept. de Fisiopatología Celular y Molecular, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu, 9, E-28040 Madrid, Spain. Tel.: 34-91-837-3112 (ext. 4217); Fax: 34-91-536-0432; E-mail: jmrojo{at}cib.csic.es.

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