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Severely Impaired Clonal Deletion of CD4⁺ T Cells in Low-Dose Irradiated Mice: Role of T Cell Antigen Receptor and IL-7 Receptor Signals¹

Centenary Institute of Cancer Medicine and Cell Biology, Faculty of Medicine, University of Sydney, Newtown, New South Wales, Australia

Systemic administration of high doses of soluble Ag induces peripheral CD4⁺ T cell tolerance in unmanipulated hosts. To test whether tolerance is modified under conditions of transient lymphopenia, we tracked the response of 5C.C7 TCR-transgenic CD4⁺ T cells to i.v. moth cytochrome c peptide in mice that received low-dose gamma irradiation 10 days previously. This model was chosen because it does not support spontaneous lymphopenia-induced proliferation of 5C.C7 cells, allowing the study of Ag-specific responses without interference from simultaneous spontaneous proliferation. Clonal expansion in response to i.v. peptide was increased in irradiated mice, while clonal deletion was severely impaired in comparison with untreated animals. Amplified TCR triggering was observed in irradiated hosts, consistent with dendritic cell activation leading to enhanced Ag presentation. Failure of deletion was accompanied by persistent T cell activation and accumulation of Th1 effector cells. Up-regulated expression of IL-7R and the prosurvival protein Bcl-x_L was associated with clonal persistence. Cells with memory and naive phenotypes were both represented within persistent clones, but no Th1 function could be demonstrated within the long-term memory population. Failure of clonal deletion in irradiated hosts represents a novel mechanism limiting TCR diversity in a lymphopenic environment and may contribute to subsequent autoimmunity.

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 B.F.d.S.G. was supported by a National Health and Medical Research Council of Australia Principal Research Fellowship. This work was funded by a Program grant from the National Health and Medical Research Council of Australia. The support of the New South Wales Health Department through its Research and Infrastructure Grants Programme is gratefully acknowledged.

² Address correspondence and reprint requests to Prof. Barbara Fazekas de St. Groth, Centenary Institute of Cancer Medicine and Cell Biology, Faculty of Medicine, University of Sydney, Locked Bag No.6, Newtown, New South Wales, Australia 2042.

³ Abbreviations used in this paper: LIP, lymphopenia-induced proliferation; MCC, moth cytochrome c; LN, lymph node; MCCp, MCC peptide; DC, dendritic cell; Cp, proliferative capacity; _c, common -chain; TSLP, thymic stromal lymphopoietin.

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