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TGF-1 Regulates Antigen-Specific CD4⁺ T Cell Responses in the Periphery¹

Department of Pathology and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756

T cell expansion typically is due to cognate interactions with specific Ag, although T cells can be experimentally activated through bystander mechanisms not involving specific Ag. TGF-1 knockout mice exhibit a striking expansion of CD4⁺ T cells in the liver by 11 days of age, accompanied by CD4⁺ T cell-dependent necroinflammatory liver disease. To examine whether hepatic CD4⁺ T cell expansion in TGF-1^–/– mice is due to cognate TCR-peptide interactions, we used spectratype analysis to examine the diversity in TCR V repertoires in peripheral CD4⁺ T cells. We reasoned that Ag-nonspecific T cell responses would yield spectratype profiles similar to those derived from control polyclonal T cell populations, whereas Ag-specific T cell responses would yield perturbed spectratype profiles. Spleen and liver CD4⁺ T cells from 11-day-old TGF-1^–/– mice characteristically exhibited highly perturbed nonpolyclonal distributions of TCR V CDR3 lengths, indicative of Ag-driven T cell responses. We quantitatively assessed spectratype perturbation to derive a spectratype complexity score. Spectratype complexity scores were considerably higher for TGF-1^–/– CD4⁺ T cells than for TGF-1^+/– CD4⁺ T cells. TCR repertoire perturbations were apparent as early as postnatal day 3 and preceded both hepatic T cell expansion and liver damage. By contrast, TGF-1^–/– CD4⁺ single-positive thymocytes from 11-day-old mice exhibited normal unbiased spectratype profiles. These results indicate that CD4⁺ T cells in TGF-1^–/– mice are activated by and respond to self-Ags present in the periphery, and define a key role for TGF-1 in the peripheral regulation of Ag-specific CD4⁺ T cell responses.

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¹ This work was supported by National Institutes of Health Grants AI053056 and DK073904 and P20RR16437 from the COBRE Program of the National Center for Research Resources.

² Address correspondence and reprint requests to Dr. James D. Gorham, Department of Pathology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756. E-mail address: James.D.Gorham{at}Dartmouth.edu

³ Abbreviations used in this paper: CD62L, CD62 ligand; Treg, regulatory T cells; CD4SP, CD4⁺ single positive; MNC, mononuclear cell; ALT, alanine aminotransferase; SC, spectratype complexity.