TGF-beta 1 regulates antigen-specific CD4+ T cell responses in the periphery

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• T cell activation is typically antigen-specific but can occur via bystander mechanisms.
• Transforming growth factor-beta1 (TGF-beta1) knockout mice develop CD4+ T cell expansion and liver disease.
• The mechanism driving this T cell expansion in TGF-beta1(-/-) mice is unclear.

Purpose of the Study:

• To investigate whether hepatic CD4+ T cell expansion in TGF-beta1 knockout mice results from antigen-specific T cell receptor (TCR) interactions.
• To analyze the T cell receptor Vbeta repertoire diversity in peripheral CD4+ T cells of TGF-beta1 knockout mice.

Main Methods:

• Spectratype analysis of TCR Vbeta repertoires in spleen and liver CD4+ T cells.
• Quantitative assessment of spectratype perturbation using a spectratype complexity score.
• Comparison of T cell repertoires between TGF-beta1 knockout and control mice.

Main Results:

• TGF-beta1 knockout mice exhibited highly perturbed, nonpolyclonal TCR Vbeta CDR3 length distributions in liver and spleen CD4+ T cells.
• Spectratype complexity scores were significantly higher in TGF-beta1 knockout mice compared to controls.
• TCR repertoire perturbations were observed as early as postnatal day 3, preceding liver pathology.

Conclusions:

• Hepatic CD4+ T cell expansion in TGF-beta1 knockout mice is driven by antigen-specific responses to self-antigens.
• TGF-beta1 plays a critical role in the peripheral regulation of antigen-specific CD4+ T cell responses.