The Journal of Experimental Medicine
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Published online 28 May 2002 doi:10.1084/jem.20020119
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© Rockefeller University Press, 0022-1007/2002/6/1419/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 11, June 3, 2002 1419-1431

Involvement of the TCR Cß FG Loop in Thymic Selection and T Cell Function

Tetsuro Sasada1,2, Maki Touma1,2, Hsiu-Ching Chang1,2, Linda K. Clayton1,2, Jia-huai Wang1,3,4 and Ellis L. Reinherz1,2

1 Laboratory of Immunobiology, Dana-Farber Cancer Institute
2 Department of Medicine, Harvard Medical School, Boston, MA 02115
3 Department of Pediatrics, Harvard Medical School, Boston, MA 02115
4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115

Address correspondence to Dr. Ellis L. Reinherz, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: 617-632-3412; Fax: 617-632-3351; E-mail: ellis_reinherz{at}dfci.harvard.edu

The asymmetric disposition of T cell receptor (TCR) Cß and C{alpha} ectodomains creates a cavity with a side-wall formed by the rigid Cß FG loop. To investigate the significance of this conserved structure, we generated loop deletion (ß{Delta}FG) and ßwt transgenic (tg) mice using the TCR ß subunit of the N15 CTL. N15ßwt and N15ß{Delta}FG H-2b animals have comparable numbers of thymocytes in S phase and manifest developmental progression through the CD4-CD8- double-negative (DN) compartment. N15ß{Delta}FG facilitates transition from DN to CD4+8+ double-positive (DP) thymocytes in recombinase activating gene (RAG)-2-/- mice, showing that pre-TCR function remains. N15ß{Delta}FG animals possess ~twofold more CD8+ single-positive (SP) thymocytes and lymph node T cells, consistent with enhanced positive selection. As an altered V{alpha} repertoire observed in N15ß{Delta}FG mice may confound the deletion's effect, we crossed N15{alpha}ß TCR tg RAG-2-/- with N15ß{Delta}FG tg RAG-2-/- H-2b mice to generate N15{alpha}ß RAG-2-/- and N15{alpha}ß.ß{Delta}FG RAG-2-/- littermates. N15{alpha}ß.ß{Delta}FG RAG-2-/- mice show an 8–10-fold increase in DP thymocytes due to reduced negative selection, as evidenced by diminished constitutive and cognate peptide-induced apoptosis. Compared with N15{alpha}ß, N15{alpha}ß.ß{Delta}FG T cells respond poorly to cognate antigens and weak agonists. Thus, the Cß FG loop facilitates negative selection of thymocytes and activation of T cells.

Key Words: negative selection • thymocyte development • TCR structure • Ig superfamily • transgenic mice


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