Abstract
Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings.
Highlights
FoxP3-expressing regulatory T-cells (Treg) maintain tolerance to self and to the environment, and are central players in the control of immune responses in general [1]
Adults submitted to total thymectomy early in life provide a unique setting to investigate human naïve compartment homeostasis
We applied here strict criteria to exclude residual thymic activity based on detailed surgical reports and single-joint T-cell receptor (TCR) excision circles levels clearly below the lowest level observed in healthy adults (Table 1). sjTRECs are by-products of TCR rearrangements during T-cell development that are progressively lost as cells divide in the periphery, and used to identify recent thymic emigrant cells [24]
Summary
FoxP3-expressing regulatory T-cells (Treg) maintain tolerance to self and to the environment, and are central players in the control of immune responses in general [1]. Notwithstanding their relevance in limiting immunemediated pathology, and their therapeutic potential, research focused on human Treg homeostasis has been scarce [2]. The establishment and maintenance of the human naïve T-cell compartment is known to rely on both thymic output and peripheral expansion, with their relative contributions still the subject of intense debate. Increasing evidence points to a major contribution of peripheral proliferation in order to explain the relatively stable size of the naïve compartment in adulthood despite thymic involution [9, 10]
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