Role of cytokines in thymus- versus peripherally derived-regulatory T cell differentiation and function

Abstract

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are essential players in the control of immune responses. Recently, accordingly to their origin, two main subsets of Tregs have been described: thymus-derived Tregs (tTregs) and peripherally derived Tregs (pTregs). Numerous signaling pathways including the IL-2/STAT5 or the TGF-β/Smad3 pathways play a crucial role in segregating the two lineages. Here, we review some of the information existing on the distinct requirements of IL-2, TGF-β, and TNF-α three major cytokines involved in tTreg and pTreg generation, homeostasis and function. Today it is clear that signaling via the IL-2Rβ chain (CD122) common to IL-2 and IL-15 is required for proper differentiation of tTregs and for tTreg and pTreg survival in the periphery. This notion has led to the development of promising therapeutic strategies based on low-dose IL-2 administration to boost the patients' own Treg compartment and dampen autoimmunity and inflammation. Also, solid evidence points to TGF-β as the master regulator of pTreg differentiation and homeostasis. However, therapeutic administration of TGF-β is difficult to implement due to toxicity and safety issues. Knowledge on the role of TNF-α on the biology of Tregs is fragmentary and inconsistent between mice and humans. Moreover, emerging results from the clinical use of TNF-α inhibitors indicate that part of their anti-inflammatory effect may be dependent on their action on Tregs. Given the profusion of clinical trials testing cytokine administration or blocking to modulate inflammatory diseases, a better knowledge of the effects of cytokines on tTregs and pTregs biology is necessary to improve the efficiency of these immunotherapies.

Keywords: Foxp3; IL-2; TGF-β; TNF-α; pTreg; regulatory T cells; tTreg.

Figure 1

A hypothetic model for tTreg differentiation in the thymus. (A) Immature CD4⁺ thymocytes are engaged by strong agonist TCR/co-stimulatory signals, which results in the expression of the IL2R alpha chain CD25. (B) Subsequent interaction of immature tTreg precursors with CD122 signaling cytokines IL-2 and IL-15 leads to STAT5 phosphorylation to generate tTreg precursors. (C) Following continuous engagement of CD122, Foxp3 expression is induced in tTreg precursors to generate fully mature tTregs.

Figure 2

IL-2 favors the generation and increases the stability of the pTreg phenotype. (A) Activation of a naive conventional T cells through TCR stimulation and in the presence of TGF-β leads to generation of unstable pTregs that express moderate levels of Foxp3 and CD25. (B) In the presence of IL-2, pTregs increase the expression levels of Foxp3 and CD25 and the pTreg phenotype is stabilized. (C) During inflammation and in the absence of IL-2, the pTregs convert into “ex-pTregs” that can produce different pro-inflammatory cytokines, such as IFN-γ or IL-17 depending on the environmental context.