Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 195, Issue 11, Pages 1419-1431Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20020119
Keywords
negative selection; thymocyte development; TCR structure; Ig superfamily; transgenic mice
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Funding
- NIAID NIH HHS [R56 AI019807, AI 39098, R01 AI019807, R37 AI019807, AI 19807] Funding Source: Medline
- NIGMS NIH HHS [GM 56008] Funding Source: Medline
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The asymmetric disposition of T cell receptor (TCR) Cbeta and Calpha ectodomains creates a cavity with a side-wall formed by the rigid Cbeta FG loop. To investigate the significance of this conserved structure, we generated loop deletion (betaDeltaFG) and betawt transgenic (tg) mice using the TCR P subunit of the N15 CTL. N15betawt and N15betaDeltaFG H-2(b) animals have comparable numbers of thymocytes in S phase and manifest developmental progression through the CD4(-)CD8(-) double-negative (DN) compartment. N15betaDeltaFG facilitates transition from DN to CD4(+)8(+) double-positive (DP) thymocytes in recombinase activating gene (RAG)-2(-/-) mice, showing that pre-TCR function remains. N15betaDeltaFG animals possess similar totwofold more CD8(+) single-positive (SP) thymocytes and lymph node T cells, consistent with enhanced positive selection. As an altered Vet repertoire observed in N15betaDeltaFG mice may confound the deletion's effect, we crossed N15alphabeta TCR tg RAG-2(-/-) with N15betaDeltaFG tg RAG-2(-/-) H-2(b) mice to generate N15alphabeta RAG-2(-/-) and N15alphabeta.betaDeltaFG RAG-2(-/-) littermates. N15alphabeta.betaDeltaFG 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 N15alphabeta, N15alphabeta.betaDeltaFG T cells respond poorly to cognate antigens and weak agonists. Thus, the Cbeta FG loop facilitates negative selection of thymocytes and activation of T cells.
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