Extrathymic induction of Foxp3⁺ regulatory T cells declines with age in a T‐cell intrinsic manner

Abstract

Extrathymically induced Foxp3+ regulatory T (Treg) cells contribute to the pool of Treg cells and are implicated in the maintenance of immune tolerance at environmental interfaces. The impact of T-cell senescence on their generation and function is, however, poorly characterized. We report here that steady-state induction of Foxp3 is impaired in aged T cells in vivo. In vitro assays further revealed that this defective generation of Treg cells was independent from the strength of TCR stimulation and arose before T-cell proliferation. Importantly, they also revealed that this impairment of Foxp3 induction is unrelated to known age-related T-cell defects, such as IL-2 secretion impairment, accumulation of activated T-cell populations, or narrowing of the T-cell repertoire. Finally, a loss of extrathymic induction of Foxp3 and tolerance to minor-mismatched skin graft were observed in aged mice treated by nondepleting anti-CD4 antibody. The T-cell intrinsic impairment of Treg-cell generation revealed here highlights age as a key factor to be considered in immune tolerance induction. [5,6], and in pregnancy [7,8] in which pTreg cells allow the development of a suppressive T-cell repertoire adapted to evolving antigens encountered in the periphery. Aging is associated with altered immune responses to vaccination, infection, cancer, and dysregulation of inflammatory responses [9,10]. In addition to a decrease in naïve T-cell numbers due to thymus involution [11,12], functional impairment of T cells is a major component of the defective immune response in the elderly [13]. In particular, an early and transient IL-2 secretion defect in aged T cells leads to impaired proliferation and differentiation in fully functional Th1 and Th2 cells [14,15]. We characterized here the effect of T-cell senescence on pTreg-cell generation and report that T-cell intrinsic defects oppose the induction of Foxp3 in aged Tconv cells both at the steady state and during induction of transplantation tolerance. Results and discussion Impaired Foxp3 induction in vivo at the steady state in aged T cellsTo explore whether T-cell senescence affects pTreg production, we first compared in vivo Foxp3 induction at the steady state in Tconv populations isolated from either young (5-20 weeks) or old (60-65 weeks) Foxp3-eGFP mice. Highly purified CD4 + eGFP − T cells (>99.99%) from young Foxp3-eGFP mice ( Fig. 1A) were transferred into C57Bl/6 CD45.1 + congenic hosts, and 4 weeks after transfer, 0.4% of eGFP + cells was detected in the donor T-cell population (Fig. 1B). In contrast, a 1. A straightforward explanation for the defective pTreg-cell production observed in aged mice could be the progressive disappearance from the periphery of recent thymic emigrants (RTE) enriched in pTreg-cell precursors [17,18]. Precise time-course experiments effectively revealed that pTreg-cell generation was higher in 2-week Tconv cells, which are enriched in RTE, and comparable with that of thymocytes (Fig. 1D). This is consistent with an RTE-dependent conversion process...

Foxp3+ regulatory T‐cell homeostasis quantitatively differs in murine peripheral lymph nodes and spleen

“…Our results shed light on a fundamental part of Treg-cell homeostasis, which is the extrathymic generation of Treg cells. A basal level of conversion takes place in steady state, which is in accordance with the hypothesis that peripheral homeostasis depends on presentation of self, food, and flora-derived antigens under tolerogenic conditions, leading to conversion of Tnaive cells into pTreg cells [18,52,53]. Here we observed again an essential difference between LNs and spleen.…”

Age-Dependent Changes in Regulatory T Lymphocyte Development and Function: A Mini-Review

“…Peripheral Treg induction therefore presumably decreases in parallel to thymic involution and Tconv production. However, Carpentier et al [26] have shown that differentiation of naïve Tconv from old mice into Treg is less efficient both in vitro and in vivo. The defective production of pTreg in the elderly may be due to a T-cell-intrinsic factor [26] .…”

“…However, Carpentier et al [26] have shown that differentiation of naïve Tconv from old mice into Treg is less efficient both in vitro and in vivo. The defective production of pTreg in the elderly may be due to a T-cell-intrinsic factor [26] . It appears therefore that the peripheral differentiation of pTreg drops with age because of a combination of reduced thymic output and potentially thymocyte-intrinsic factors.…”

Myocardial aging as a T-cell–mediated phenomenon

“…Furthermore, myocardial senescence is associated with cardiomyocyte cell death, leading to increased exposure of heartspecific antigens to immune cells (26). From the immunological perspective, aging is accompanied by an increased systemic inflammatory basal tone (27)(28)(29) and with defective maintenance of immunological tolerance (30)(31)(32).…”