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© The Rockefeller University Press, 0022-1007/1998/10/1239/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 7, October 5, 1998 1239-1246

Articles

Cytotoxic T Lymphocyte Antigen 4 Is Induced in the Thymus upon In Vivo Activation and Its Blockade Prevents Anti-CD3–mediated Depletion of Thymocytes

Corrado M. Cilio*, Michael R. Daws{ddagger}, Anna Malashicheva*, Charles L. Sentman{ddagger}, and Dan Holmberg*

From the * Department for Cell and Molecular Biology, {ddagger} Umeå Center for Molecular Pathogenesis, Umeå University, S-901 87 Umeå, Sweden

The development of a normal T cell repertoire in the thymus is dependent on the interplay between signals mediating cell survival (positive selection) and cell death (negative selection or death by neglect). Although the CD28 costimulatory molecule has been implicated in this process, it has been difficult to establish a role for the other major costimulatory molecule, cytotoxic T lymphocyte antigen (CTLA)-4. Here we report that in vivo stimulation through the T cell receptor (TCR)–CD3 complex induces expression of CTLA-4 in thymocytes and leads to the association of CTLA-4 with the SH2 domain–containing phosphatase (SHP)-2 tyrosine phosphatase. Moreover, intrathymic CTLA-4 blockade dramatically inhibits anti-CD3–mediated depletion of CD4+CD8+ double positive immature thymocytes. Similarly, anti-CD3–mediated depletion of CD4+CD8+ double positive cells in fetal thymic organ cultures could also be inhibited by anti–CTLA-4 antibodies. Thus, our data provide evidence for a role of CTLA-4 in thymic selection and suggest a novel mechanism contributing to the regulation of TCR-mediated selection of T cell repertoires.

Key Words: cytotoxic T lymphocyte antigen 4 (CD152) • CD28 • costimulation • T cell development • tyrosine phosphatase SHP-2

Address correspondence to Dan Holmberg, Department for Cell and Molecular Biology, Umeå University, S-901 87 Umeå, Sweden. Phone: 46-90-785-2702; Fax: 46-90-77-14-20; E-mail: dan.holmberg{at}cmb.umu.se

A. Malashicheva's present address is Institute of Cytology, Russian Academy of Science, Tichozetzky p2.4, 194064 St. Petersburg, Russia.

Abbreviations used: DN, double negative; DP, double positive; FTOC, fetal thymic organ culture; RT, reverse transcriptase; SHP, SH2 domain–containing phosphatase; SP, single positive.


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