Defective cell death signalling along the Bcl-2 regulated apoptosis pathway compromises Treg cell development and limits their functionality in mice

Tischner, Denise; Gaggl, Irene; Peschel, Ines; Kaufmann, Manuel; Tuzlak, Selma; Drach, Mathias; Thuille, Niκolaus; Wiegers, G. Jan

doi:10.1016/j.jaut.2011.12.008

Cited by 38 publications

(31 citation statements)

References 49 publications

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“…On the other hand, recent studies have shown that Foxp3 + expression protects T reg cells from activation-induced cell death (46). A differential expression of the BimYBcl-2 axis in T reg cells and T con cells was suspected to contribute to apoptosis resistance of T reg cells (47,48) but was not found to be the case in our study (data not shown). A most recent study suggests that Mcl-1, but not Bcl-x L or Bcl-2, is essential for T reg cell survival (49).…”

Section: Discussioncontrasting

confidence: 76%

CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells

et al. 2014

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Section: Discussioncontrasting

confidence: 76%

CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells

et al. 2014

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“…It has been reported that A1 mRNA levels are high in splenic Tregs but even higher in thymic Tregs when compared with the expression observed in CD4 + Tcons. 34 However, this was not demonstrated at the protein level in this study. Our results nonetheless support similar or even lower protein expression levels of A1 in Tregs compared with Tcons.…”

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confidence: 68%

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection

et al. 2017

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The physiological role of the pro-survival BCL-2 family member A1 has been debated for a long time. Strong mRNA induction in T cells on T cell receptor (TCR)-engagement suggested a major role of A1 in the survival of activated T cells. However, the investigation of the physiological roles of A1 was complicated by the quadruplication of the A1 gene locus in mice, making A1 gene targeting very difficult. Here, we used the recently generated A1−/− mouse model to examine the role of A1 in T cell immunity. We confirmed rapid and strong induction of A1 protein in response to TCR/CD3 stimulation in CD4 + as well as CD8 + T cells. Surprisingly, on infection with the acute influenza HKx31 or the lymphocytic choriomeningitis virus docile strains mice lacking A1 did not show any impairment in the expansion, survival, or effector function of cytotoxic T cells. Furthermore, the ability of A1 −/− mice to generate antigen-specific memory T cells or to provide adequate CD4-dependent help to B cells was not impaired. These results suggest functional redundancy of A1 with other pro-survival BCL-2 family members in the control of T celldependent immune responses. Cell Death and Differentiation (2017) 24, 523-533; doi:10.1038/cdd.2016.155; published online 13 January 2017On antigenic challenge, T lymphocytes need to rapidly switch from their IL-7/IL-7R-regulated naive, quiescent state 1,2 to a T cell antigen-receptor (TCR/CD3) stimulation-induced activation state. 3 In case of inappropriate stimulation of the TCR, for example, in the absence of co-receptor stimulation, this shift in the survival programme is not induced and leads to rapid T cell death. 4 Conversely, appropriately stimulated T cells expand rapidly, allowing accumulation of T cell clones expressing TCRs of high affinity for specific antigens. During this clonal expansion, BCL-2 family regulated apoptosis acts as a mechanism to remove low-affinity T cells, thereby ensuring the generation of a highly effective immune response.5 On infection clearance, most of the activated T cells are removed by apoptosis, 6 leaving only some T cells with antigen-specific high-affinity TCRs in reserve as longlived memory T cells. 7The BCL-2 family of proteins regulate apoptotic cell death, with the balance between pro-survival and pro-apoptotic family members determining whether a cell lives or dies. The expression of pro-survival BCL-2 family members is dynamically regulated during T cell activation.8 TCR/CD3 ligation leads to the downregulation of BCL-2 and induction of BCL-XL.3 Accordingly, Bcl-2 −/− mice display a loss of mature, unstimulated T cells, and the death of these cells can be prevented by TCR/CD3 stimulation.9 Interestingly, although BCL-XL is substantially upregulated on TCR/CD3 stimulation, its loss did not increase apoptosis or impair proliferation of T cells stimulated with mitogenic antibodies. 10 In contrast, MCL-1 has been shown to be a crucial pro-survival factor after T cell activation.11,12 A1 is a prosurvival BCL-2 family protein that has been proposed to be i...

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“…Interestingly, extrathymic Treg-cell production was shown to be of importance to control inflammatory Th2 responses at environmental interfaces and commensal microbiota composition [26]. The age-related defect in Foxp3 induction identified here can explain why Treg cells fail to control dysregulated inflammation found at mucosal sites in elderly [10,27] despite a global accumulation of Treg cells, due to their increased resistance to apoptosis [28]. Our findings indicate that impairment of extrathymic induction of Foxp3 with age is an important feature, which may compromise the success of tolerance induction protocols in elderly.…”

Section: Discussionmentioning

confidence: 79%

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

et al. 2013

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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...

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Defective cell death signalling along the Bcl-2 regulated apoptosis pathway compromises Treg cell development and limits their functionality in mice

Cited by 38 publications

References 49 publications

CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells

CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection

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

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Defective cell death signalling along the Bcl-2 regulated apoptosis pathway compromises Treg cell development and limits their functionality in mice

Cited by 38 publications

References 49 publications

CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells

CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection

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

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