期刊
JOURNAL OF IMMUNOLOGY
卷 179, 期 1, 页码 71-79出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.179.1.71
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- NCRR NIH HHS [P20 RR 16437] Funding Source: Medline
- NIAID NIH HHS [AI 053056] Funding Source: Medline
- NIDDK NIH HHS [DK 073904] Funding Source: Medline
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-beta 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-beta 1(-/-) mice is due to cognate TCR-peptide interactions, we used spectratype analysis to examine the diversity in TCR V beta 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-beta 1(-/-) mice characteristically exhibited highly perturbed nonpolyclonal distributions of TCR V beta 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-beta 1(-/-) CD4(+) T cells than for TGF-beta 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-beta 1(-/-) CD4(+) single-positive thymocytes from 11-day-old mice exhibited normal unbiased spectratype profiles. These results indicate that CD4(+) T cells in TGF-beta 1(-/-) mice are activated by and respond to self-Ags present in the periphery, and define a key role for TGF-beta 1 in the peripheral regulation of Ag-specific CD4(+) T cell responses.
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