Molecular mechanisms of treg-mediated T cell suppression

Abstract

CD4(+)CD25(high)Foxp3(+) regulatory T cells (Tregs) can suppress other immune cells and, thus, are critical mediators of peripheral self-tolerance. On the one hand, Tregs avert autoimmune disease and allergies. On the other hand, Tregs can prevent immune reactions against tumors and pathogens. Despite the importance of Tregs, the molecular mechanisms of suppression remain incompletely understood and controversial. Proliferation and cytokine production of CD4(+)CD25(-) conventional T cells (Tcons) can be inhibited directly by Tregs. In addition, Tregs can indirectly suppress Tcon activation via inhibition of the stimulatory capacity of antigen presenting cells. Direct suppression of Tcons by Tregs can involve immunosuppressive soluble factors or cell contact. Different mechanisms of suppression have been described, so far with no consensus on one universal mechanism. Controversies might be explained by the fact that different mechanisms may operate depending on the site of the immune reaction, on the type and activation state of the suppressed target cell as well as on the Treg activation status. Further, inhibition of T cell effector function can occur independently of suppression of proliferation. In this review, we summarize the described molecular mechanisms of suppression with a particular focus on suppression of Tcons and rapid suppression of T cell receptor-induced calcium (Ca(2+)), NFAT, and NF-κB signaling in Tcons by Tregs.

Keywords: TCR signaling; Treg; suppression mechanisms.

Figure 1

Mechanisms of Treg-mediated Tcon suppression. Tregs have been described to suppress Tcons by different mechanisms, depending on the experimental setup, site and type of immune response. Tregs can generate immunosuppressive adenosine or transfer cAMP to Tcons. Tregs can rapidly suppress TCR-induced Ca²⁺, NFAT, and NF-κB signaling. Tregs can also produce immunosuppressive cytokines (IL-10, TGF-β, IL-35), and they can suppress by IL-2 consumption or induce effector cell death via granzyme and perforin. Furthermore, Tregs can suppress Tcons indirectly by downregulating costimulatory molecules on APCs (such as DCs) via CTLA-4. Details are described in the text.

Figure 2

Simplified view of  TCR signaling in T cells. After TCR stimulation, several pathways are initiated which ultimately result in T cell activation, proliferation and expression of cytokines such as IL-2 and IFN-γ. The main transcription factors involved are AP-1, NFAT, and NF-κB. AP-1 is activated by a MAPK cascade. NF-κB is activated by PKCθ-dependent activation of the IKK complex and subsequent IκB degradation, and Ca²⁺ also contributes to NF-κB activation. NFAT is activated by Ca²⁺ influx which activates the NFAT-dephosphorylating phosphatase calcineurin. Only the major pathways are displayed here and represent a simplified view of TCR signaling. Details are described in the text.

Figure 3

Tregs suppress particular TCR signaling pathways in Tcons. Activated Tregs rapidly suppress cytokine expression in Tcons via inhibition of Ca²⁺ signals and consequently reduced NF-κB and NFAT activation. Suppression by Tregs requires at least 30 min of coculture, is favored by cell contact and sustained after Treg removal. Red indicates Treg-mediated suppression of TCR-induced activation in Tcons. Molecules displayed in green were not inhibited during Treg-mediated rapid suppression of cytokine transcription. Molecules in gray were not analyzed or TCR-induced activation was not detectable.