IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes

Abstract

Development of Foxp3-expressing regulatory T-lymphocytes (Treg) in the thymus is controlled by signals delivered in T-cell precursors via the TCR, co-stimulatory receptors, and cytokine receptors. In absence of IL-2, IL-15 or their receptors, fewer Treg apparently develop in the thymus. However, it was recently shown that a substantial part of thymic Treg are cells that had recirculated from the periphery back to the thymus, troubling interpretation of these results. We therefore reassessed the involvement of IL-2 and IL-15 in the development of Treg, taking into account Treg-recirculation. At the age of three weeks, when in wt and IL-15-deficient (but not in IL-2-deficient) mice substantial amounts of recirculating Treg are present in the thymus, we found similarly reduced proportions of newly developed Treg in absence of IL-2 or IL-15, and in absence of both cytokines even less Treg developed. In neonates, when practically no recirculating Treg were found in the thymus, the absence of IL-2 led to substantially more reduced Treg-development than deficiency in IL-15. IL-2 but not IL-15 modulated the CD25, GITR, OX40, and CD73-phenotypes of the thymus-egress-competent and periphery-seeding Treg-population. Interestingly, IL-2 and IL-15 also modulated the TCR-repertoire expressed by developing Treg. Upon transfer into Treg-less Foxp3sf mice, newly developed Treg from IL-2- (and to a much lesser extent IL-15-) deficient mice suppressed immunopathology less efficiently than wt Treg. Taken together, our results firmly establish important non-redundant quantitative and qualitative roles for IL-2 and, to a lesser extent, IL-15 in intrathymic Treg-development.

Ageing Affects Thymopoiesis and Experimental Autoimmune Encephalomyelitis Development in a Strain-Dependent Manner

“…This difference seems to be consistent with impaired thymocyte-negative selection even in early DP developmental stage in old AO compared with DA rats [77, 90]. In the same vein was the opposite effects of ageing (viz., age-related increase and decrease in DA and AO rats, respectively) on the expression of IL-15, a cytokine also involved in intrathymic nTreg development [91] in AO and DA rats. Moreover, it is noteworthy that in DA rats age-related decline in the total thymocyte yield was steeper than in AO rats whereas on the contrary, age-related decrease in the overall absolute number of nTregs was steeper in AO rats compared with DA ones, thereby additionally supporting their putative role in the increased propensity of old AO rats for development of clinically manifested disease.…”

Role of Treg cell subsets in cardiovascular disease pathogenesis and potential therapeutic targets

“…Immune suppressive regulatory T lymphocytes expressing the transcription factor Foxp3 play an essential role in maintaining immune tolerance to self and benign non-self antigens (47). For most Tregs, differentiation requires antigenic signals from T cell receptors, costimulatory molecules, and signals from cytokine receptors like IL-2 (48,49). Thus, by competitively utilizing IL-2, Treg cells interfere with the maturation of responsive T cells, leading to T cell apoptosis and suppression (47,50).…”

Adjusting to self in the thymus: CD4 versus CD8 lineage commitment and regulatory T cell development

“…While IL2 plays a central role in thymic Treg development, other related cytokines can support Treg development and appear to favor distinct developmental pathways and TCR specificities. Most notably, the STAT5-activating cytokine IL15 ( Box 6 ) is a significant player, with mutations that disrupt both IL2 and IL15 signaling leading to a much greater reduction in thymic Tregs than mutations of IL2 alone ( Apert et al, 2022 ; Burchill et al, 2007 , 2008 ; Fontenot et al, 2005 ; Lio and Hsieh, 2008 ; Soper et al, 2007 ; Vang et al, 2008 ). Moreover, in apparent contradiction to the two-step model, which posits that CD25 induction is required prior to FoxP3 upregulation, the thymus contains a substantial population of developing Tregs that lack CD25 but express FoxP3 ( Marshall et al, 2014 ; Owen et al, 2019a ).…”