TGF-β1 Regulates Antigen-Specific CD4+ T Cell Responses in the Periphery

Abstract

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-β1 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-β1−/− mice is due to cognate TCR-peptide interactions, we used spectratype analysis to examine the diversity in TCR Vβ 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-β1−/− mice characteristically exhibited highly perturbed nonpolyclonal distributions of TCR Vβ 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-β1−/− CD4+ T cells than for TGF-β1+/− 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-β1−/− CD4+ single-positive thymocytes from 11-day-old mice exhibited normal unbiased spectratype profiles. These results indicate that CD4+ T cells in TGF-β1−/− mice are activated by and respond to self-Ags present in the periphery, and define a key role for TGF-β1 in the peripheral regulation of Ag-specific CD4+ T cell responses.

TGF-β: Guardian of T Cell Function

“…In the absence of TGF-β, IL-7Rα expression positively correlated with TCR affinity, as TGF-βRII-deficient T cells bearing higher affinity TCRs expressed increased amounts of IL-7Rα (and thus exhibited better homeostatic survival) than their lower affinity counterparts. Accordingly, a report that TCR diversity is altered only in the periphery, and not the thymus, of Tgfb1 −/− mice likely reflects repertoire changes resulting from preferential loss of low affinity T cells (23). TGF-β maintenance of low affinity T cells may also be important for a novel regulatory population of “deletor” CD4 + T cells that restricts antigen-specific T cells by competing for endogenous self-peptides, including low affinity ligands that may mediate positive selection (24).…”

NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human

“…RNA was isolated from these purified cells with the RNeasy Mini Kit (Qiagen), and cDNA was synthesized with random hexamers (Invitrogen) from the RNA. The cDNA was used for PCR amplification of 24 TCR Vβs using spectratyping primers as previously reported (61).…”

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…Thus, the absence of TGF-b signaling causes a more profound defect in IL-7Ra expression and correspondingly results in poor peripheral homeostasis in T cells bearing low-affinity TCRs. Notably, Tgfb1 2/2 mice show altered diversity of CD4 þ TCRs in the periphery, but not in the thymus (Robinson and Gorham 2007), which likely reflects repertoire changes caused by the preferential loss of lowaffinity CD4 þ T cells.…”