TGFbeta1 and Treg cells: alliance for tolerance

Abstract

Transforming growth factor beta1 (TGFbeta1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (Treg)-cell and effector-cell function and tumorigenesis. Defects in TGFbeta1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFbeta1 prevents abnormal T-cell activation through the modulation of Ca2+-calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in Treg cells, its effects are mediated, at least in part, through SMAD signaling. TGFbeta1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (Th IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFbeta1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.

Figure 1

Cross-talk between TCR and TGFβ signaling networks. TCR activation on recognition of MHC–Ag complexes on APCs leads to the phosphorylation of ZAP70, PLCγ and Lck. PLCγ hydrolyses PIP₂ to generate DAG and IP₃. DAG binds to and activates PKC, whereas IP₃ binds to its receptor on the endoplasmic reticulum (ER) and releases Ca²⁺ into cytoplasm. Activated PKC activates NF-κB by degrading I-κB through phosphorylation. Increased cytosolic Ca²⁺ leads to the activation of calcineurin (CN), which, in turn, activates NF-AT through dephosphorylation. Active NF-κB and NF-AT translocate to the nucleus and induce the gene transcription that is required for the T-cell response. Co-stimulatory signals through CD28 activate the JNK/p38 MAPK pathway, which activates AP-1 (FOS/JUN). CD28 co-stimulatory signals inhibit Cblb, which is a negative regulator of TCR signals. Signaling through CD28 activates AKT, which, in turn, inhibits SMAD2/3 phosphorylation. Co-stimulatory signaling through CTLA-4, which is a negative regulator of TCR signaling, induces Cblb. TGFβ-receptor signaling activates SMAD2/3 through phosphorylation. Activated SMAD2/3 binds to SMAD4 and the complex translocates to the nucleus. FOXP3 inhibits SMAD7, which is an inhibitory SMAD that inhibits TGFβ signaling. CBL-B also mediates TGFβ signaling in Foxp3 induction. CD25 is the α subunit of the high-affinity receptor for the IL-2 complex and IL-2 is essential for TGFβ1-mediated induction of FOXP3. FKBP12, which is associated with the TGFβ receptor, is released on ligand binding. FKBP12 binds to the IP₃ receptor and modulates Ca²⁺ release from ER.

Figure 2

Tolerance induction by T_reg cells. Antigen presentation by iDCs to T cells induces tolerance because iDCs do not provide co-stimulation (a). However, Ag presentation by mature DCs activates T cells and the inflammatory environment can trigger the activation of autoreactive T cells (b). (c) T_reg cells that express CTLA-4 and TGFβ1 in addition to CD28 interact with DCs and induce TGFβ1 production (conditioned DCs). Co-stimulatory molecules (CD80 and CD86) are down-modulated by TGFβ1 on conditioned DCs. Conditioned DCs induce tolerance in T cells by presenting Ag without co-stimulation and by TGFβ1 secretion.