Diversification and senescence of Foxp3⁺ regulatory T cells during experimental autoimmune encephalomyelitis

Abstract

The fate of Foxp3+ regulatory T cells (Treg) responding during autoimmunity is not well defined. We observed a marked elevation in KLRG1+ CNS-infiltrating Treg in experimental autoimmune encephalomyelitis (EAE), and assessed their origin and properties. KLRG1+ Treg showed increased activation marker expression, Foxp3 and CD25 levels, and more rapid cell cycling than KLRG1− cells. KLRG1− Treg converted into KLRG1+ cells and this was increased in the context of autoimmune inflammation. Conversion was unidirectional; KLRG1+ Treg did not revert to a KLRG1− state. KLRG1+ but not KLRG1− Treg survived poorly, indicative of terminal differentiation. This was associated with diminished BCL2 and increased apoptosis of isolated cells. KLRG1 was not upregulated on iTreg in culture, but was after transfer and EAE induction or on iTreg developing spontaneously during EAE. KLRG1+ Treg produced more IL10 and had altered effector cytokine production compared with KLRG1− Treg. Despite their differences, KLRG1+ and KLRG1− Treg proved similarly potent in suppressing EAE. KLRG1+ and KLRG1− populations were phenotypically heterogeneous, with the extent and pattern of activation marker expression dependent both on cellular location and inflammation. Our results support an extensive diversification of Treg during EAE, and associate KLRG1 with altered Treg function and senescence during autoimmunity.

LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes

“…S6). Although the activation, terminal differentiation [as marked by KLRG1 expression ( 28 )], and proliferation of Lag3 -deficient and WT Treg cells were comparable, Lag3 -deficient Treg cells expressed higher level of the anti-apoptotic factor Bcl2 in the islets (fig. S5, and S7A).…”

Lifelong training improves anti-inflammatory environment and maintains the number of regulatory T cells in masters athletes

“…Recently, the expression of KLRG1 in Tregs has been linked with altered function and senescence (Tauro et al 2013). In a model of autoimmune disease, KLRG1 + Tregs expressed higher levels of activation markers (FoxP3 and CD25) and were at a terminal differentiation stage.…”

“…TGF- triggers FoxP3 expression in precursors (CD4 + CD25 -) and together with IL-2, is a key regulator of signalling pathways that maintain FoxP3 expression and suppressive function in Tregs (Fu et al 2004;Perry et al 2013). Tregs can also express the KLRG1, a marker of senescence and differentiation of IL-10 production capacity by Tregs (Tauro et al 2013). The Killer cell lectin-like receptor G1 (KLRG1), ITIM-bearing receptor for cadherin-family proteins.…”

“…Indeed, IL-10 production by Tregs and FoxP3 expression has been shown to be preserved with aging (Jagger et al 2014). However, IL-10 expression was elevated among KLRG1+ Treg cells (Tauro et al 2013). Though KLRG1 serves as a marker for senescence, signalling through KLRG1 could result in altered T-cell function (Tauro et al 2013).…”

“…However, IL-10 expression was elevated among KLRG1+ Treg cells (Tauro et al 2013). Though KLRG1 serves as a marker for senescence, signalling through KLRG1 could result in altered T-cell function (Tauro et al 2013). Actually, KLRG1+ Treg cells are somewhat more potent than KLRG1− cells in suppressing naive T-cell proliferation in vitro (Beyersdorf et al 2007).…”