Pro-Apoptotic Protein Noxa Regulates Memory T Cell Population Size and Protects against Lethal Immunopathology

Wensveen, Felix M.; Pl, Klarenbeek; Gisbergen, Klaas P. J. M. van; Pascutti, María Fernanda; Ia, Derks; Schaik, Barbera D.C. van; Brinke, Anja ten; Vries, Niek de; D, Cekinovic; Jonjić, Stipan; Lier, R. A. W. Van; Eldering, Eric

doi:10.4049/jimmunol.1202304

Cited by 23 publications

(27 citation statements)

References 48 publications

(72 reference statements)

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“…NKG2D promotes Mcl-1 induction and enhances survival early during memory cell commitment. In accordance with our observations, mice deficient for Noxa, the proapoptotic antagonist of Mcl-1, generate more memory cells upon influenza infection (36), stressing the importance of these proteins in memory cell formation. Our findings indicate that T cell vaccines will benefit greatly from persistent low-level NKG2D signaling to maximize the number of memory precursors that is allowed to form long-term memory.…”

Section: Discussionsupporting

confidence: 76%

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Wensveen

Lenartić

Jelenčić

et al. 2013

The Journal of Immunology

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Memory formation of activated CD8 T cells is the result of a specific combination of signals that promote long-term survival and inhibit differentiation into effector cells. Much is known about initial cues that drive memory formation, but it is poorly understood which signals are essential during the intermediate stages before terminal differentiation. NKG2D is an activating coreceptor on Ag-experienced CD8 T cells that promotes effector cell functions. Its role in memory formation is currently unknown. In this study, we show that NKG2D controls formation of CD8 memory T cells by promoting survival of precursor cells. We demonstrate that NKG2D enhances IL-15–mediated PI3K signaling of activated CD8 T cells, in a specific phase of memory cell commitment, after activation but before terminal differentiation. This signal is essential for the induction of prosurvival protein Mcl-1 and precursor cell survival. In vivo, NKG2D deficiency results in reduced memory cell formation and impaired protection against reinfection. Our findings show a new role for PI3K and the NKG2D/IL-15 axis in an underappreciated stage of effector to memory cell transition that is essential for the generation of antiviral immunity. Moreover, we provide novel insights how these receptors control both effector and memory T cell differentiation.

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Section: Discussionsupporting

confidence: 76%

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Wensveen

Lenartić

Jelenčić

et al. 2013

The Journal of Immunology

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“…36,37 Noxa is activated by nutrient deprivation, potentially through maintenance of Mcl-1, 38 and can contribute to T-cell contraction in some model systems. 16,39 Further, we recently showed that Mcl-1 was critical for effector T-cell survival and that the additional loss of Bim failed to restore Mcl-1-deficient effector T-cell responses. 40 Thus, nutrients, by buffering Noxa with Mcl-1, and cytokines, by buffering Bim and Puma with Bcl-2, control the magnitude and persistence of the effector T-cell pool.…”

Section: Discussionmentioning

confidence: 99%

“…15 Noxa has a marginal role in contraction of T-cell responses. 16,17 Although Bim is the most dominant pro-apoptotic Bcl-2 family member driving contraction of T-cell responses, the study of T-cell responses to acute infection in Bim À / À mice is complicated by the ongoing autoimmune disease and altered negative selection in these mice. 18 Further, other data suggest that dendritic cell (DC) expression of Bim can control the magnitude of T-cell responses.…”

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confidence: 99%

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Kurtuluş

Sholl

et al. 2014

Cell Death Differ

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During the effector CD8 þ T-cell response, transcriptional differentiation programs are engaged that promote effector T cells with varying memory potential. Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, it is unclear if the lack of cell death enhances memory. Here, we investigated effector CD8 þ T-cell fate in mice whose death program has been largely disabled because of the loss of Bim. Interestingly, the absence of Bim resulted in a significant enhancement of effector CD8 þ T cells with more memory potential. Bim-driven control of memory T-cell development required T-cell-specific, but not dendritic cell-specific, expression of Bim. Both total and T-cell-specific loss of Bim promoted skewing toward memory precursors, by enhancing the survival of memory precursors, and limiting the availability of IL-15. Decreased IL-15 availability in Bim-deficient mice facilitated the elimination of cells with less memory potential via the additional pro-apoptotic molecules Noxa and Puma. Combined, these data show that Bim controls memory development by limiting the survival of pre-memory effector cells. Further, by preventing the consumption of IL-15, Bim limits the role of Noxa and Puma in causing the death of effector cells with less memory potential.

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“…Although it has been shown that the BIM/BCL-2 axis is a main regulator of the formation and maintenance of memory T cells, 26,27 NOXA has also been proposed to have a role in regulating the size and clonal diversity of memory T cell populations. 5,28 This is of particular interest as NOXA, like A1, is induced transcriptionally after TCR ligation. 5 NOXA is believed to antagonise MCL-1 to set a threshold for the survival of those CTLs with high-affinity TCRs.…”

mentioning

confidence: 99%

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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Pro-Apoptotic Protein Noxa Regulates Memory T Cell Population Size and Protects against Lethal Immunopathology

Cited by 23 publications

References 48 publications

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

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

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