GITR-Dependent Regulation of 4-1BB Expression: Implications for T Cell Memory and Anti–4-1BB–Induced Pathology

Lin, Gloria H. Y.; Snell, Laura M.; Wortzman, Michael E.; Clouthier, Derek L.; Watts, Tania H.

doi:10.4049/jimmunol.1201854

Cited by 36 publications

(33 citation statements)

References 53 publications

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“…IL-15 can up-regulate the expression of GITR in memory CD8 T cells [27] and the presence of GITR on memory CD8 T cells is required for their persistence in vivo [28]. Confirming previous results, we found that IL-15 increased GITR expression in a dose-dependent fashion in our model ( Figure 6).…”

Section: Role Of Gitr In Il-15 Protective Effectsupporting

confidence: 81%

“…However, significantly higher level of GITR in the presence of increasing doses of IL-15 shows that GITR could be involved in the antiapoptotic effect of IL-15. This TNFR family member is essential for the 4-1BB receptor expression on memory CD8 T cells as well as their survival in vivo [28]. GITR is also known to interact with the TNF associated factor (TRAF1, TRAF2 and TRAF3), which downstream signaling leads to enhanced survival of the CD8 memory T cells [38].…”

Section: Resultsmentioning

confidence: 99%

“…The glucocorticoid-induced TNF-related (GITR) protein is required for the survival of CD8 memory T cells in vivo [28]. GITR signaling results in NF-κB activation and a consequent upregulation of the Bcl-xL expression which is responsible for the increased survival of antigen-specific CD8 T cells [38].…”

Section: Discussionmentioning

confidence: 99%

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Corticosterone Signaling in Central Memory CD8+ T Cells Triggers Apoptosis that is Inhibited by Interleukin-15

DL¹

2015

MOJI

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Immunological memory plays a vital role in monitoring the body against specific pathogens. CD8+ memory lymphocytes allow a rapid response and elimination of any threat previously encountered in addition to keeping latent some chronic viruses in the host. However, certain situations such as chronic stress decrease immune function and could thereby promote viral reactivation. We demonstrate here that the stress hormone corticosterone, a cortisol analog in mice, induces apoptosis in CD8+ memory T cells. Interleukin-15 (IL-15), a cytokine essential for the homeostasis of memory T cells rescues corticosterone-induced apoptosis in a dose-dependent manner. IL-15 and glucocorticoid signaling pathways were investigated to explain the inhibitory effect of this cytokine. NF-κB, IκBα and Bim protein expression did not vary significantly when memory lymphocytes were cultured with corticosterone. However, expression of the glucocorticoidinduced TNFR-related protein (GITR), a member of the TNF receptor family, did significantly increase in the presence of IL-15 in a dose-dependent manner. Since GITR is required for the survival of memory CD8 T cells in vivo, this suggests that it may be involved in concert with IL-15 to counter glucocorticoid-induced apoptosis of CD8 memory T cells.

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Section: Role Of Gitr In Il-15 Protective Effectsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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Corticosterone Signaling in Central Memory CD8+ T Cells Triggers Apoptosis that is Inhibited by Interleukin-15

DL¹

2015

MOJI

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“…Agonist anti-OX40 has no effect on viral load in LCMV cl 13 infection (11), and agonist anti-4-1BB had minimal therapeutic effect when administered during the chronic stage of LCMV cl 13 infection due to the loss of a key signaling adaptor, TNFR-associated factor (TRAF)1, downstream of 4-1BB, with similar findings in T cells from chronically HIV-infected donors (12). Although anti-4-1BB demonstrated efficacy when combined with IL-7, which restores TRAF1 levels (12), there is growing concern that agonist therapies targeting T cell cosignaling molecules such as 4-1BB and CD28 or soluble factors such as IL-21 may induce indiscriminate or overzealous expansion of CD8 T cells and result in immune pathology (13)(14)(15)(16)(17)(18). Therefore, it remains a significant challenge to identify a T cell costimulatory molecule that is both safe and effective in improving immune function and control of viral infections.…”

mentioning

confidence: 79%

Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC

Clouthier

Zhou

Watts

2014

The Journal of Immunology

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The costimulatory TNFR family member GITR can provide important survival signals for CD8 T cells. However, little is known about the regulation of this pathway during a chronic infection. In this study, we show that GITR ligand (GITRL) is maximally induced on APCs at day 2 post–lymphocytic choriomeningitis virus (LCMV) clone 13 infection, but is downregulated to below baseline levels by day 8 postinfection (p.i.), and remains so at the chronic stage of infection. At its peak, GITRL expression is highest on macrophages, with lower expression on conventional and plasmacytoid dendritic cells. GITR expression was highest on T regulatory cells but was also detected on Th1 and LCMV-specific CD8 T cells at day 8 p.i. and was maintained at low, but above baseline levels at the chronic stage of LCMV infection. As GITRL was limiting at the chronic stage of infection, we investigated the potential of therapeutic stimulation of GITR at this stage using agonistic anti-GITR Ab. Anti-GITR treatment at day 21 p.i. increased the frequency and number of LCMV-specific CD8 T cells, resulting in increased in vivo CTL activity and a concomitant decrease in viral load, despite the persistence of PD-1 expression. These effects of anti-GITR were CD8 T cell intrinsic, with no detectable effects on Th1 or T regulatory cells. In contrast to other TNFR agonists, such as anti–4-1BB, which can cause immune pathology, a single therapeutic dose of anti-GITR did not induce splenomegaly or increase serum alanine transaminase. These studies identify GITR as a promising therapeutic target for chronic infection.

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“…For example, in a 3 day-bromodeoxyuridine (BrdU)-labelling analysis, the average frequency of dividing antigen-specific memory CD8 + T cells was 4% in the bone marrow and 2% in the spleen 4 . Moreover, when carboxyfluorescein succinimidyl ester (CFSE)-labelled antigen-specific memory CD8 + T cells were transferred into non-immunized animals, they showed higher rates of proliferation in the bone marrow than in the spleen and lymph nodes 3,10 . In general, the data concerning memory CD8 + T cell cycling in the bone marrow are all in agreement.…”

Section: Francesca DI Rosamentioning

confidence: 99%

Maintenance of memory T cells in the bone marrow: survival or homeostatic proliferation?

Rosa

2016

Nat Rev Immunol

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Six years ago, Radbruch and colleagues discussed in Nature Reviews Immunology (Organization of immunological memory by bone marrow stroma. Nat. Rev. Immunol. 10, 193-200 (2010)) 1 how distinct stromal cell subsets in the bone marrow can support the lifelong persistence of plasma cells and memory T cells. These authors proposed that the bone marrow might serve as a depot for resting noncirculating memory T cells. Furthermore, they discussed how memory T cells might be maintained in the bone marrow by survival factors, such as interleukin-7 (IL-7), as opposed to by proliferative factors, such as IL-15. This view was in contrast with the largely accepted notion at the time that recirculating memory T cells are maintained by a homeostatic equilibrium between proliferation and death long after antigen clearance 2 . Furthermore, it did not accommodate previous data concerning the proliferation 3,4 and recirculation 5,6 of memory CD8 + T cells in the bone marrow.Recently, the idea that was originally proposed in Nature Reviews Immunology 1 was revived by the identification of quiescent, non-migratory tissue-resident memory T (T RM ) cells in the skin, gut and other organs 7 . Indeed, Radbruch et al. hypothesized that bone marrow memory T cells might share several features with T RM cells, and they suggested that their previous and newly generated findings supported this concept 8,9 . However, it might be misleading to chiefly consider bone marrow memory T cells as non-circulating, non-dividing cells.Experiments using Ki67 staining in mice and humans have shown that, at any given time-point, 95-98% of memory CD8 + T cells in the bone marrow are in the G0 phase of the cell cycle 8,9 . Of the remaining cells, some are in the G1 interval, and a few (that is, 0.2-1.7%) are actively proliferating in S/G2/M 3,8,9 . However, this still means that the proportion of memory CD8 + T cells proliferating in the bone marrow is reproducibly two-to fourfold higher than the proportions (that is, 0.05-0.80%) proliferating in the spleen, lymph nodes or blood 3,8,9 . This is true also when cell division is measured for one or more days. For example, in a 3 day-bromodeoxyuridine (BrdU)-labelling analysis, the average frequency of dividing antigen-specific memory CD8 + T cells was 4% in the bone marrow and 2% in the spleen 4 . Moreover, when carboxyfluorescein succinimidyl ester (CFSE)-labelled antigen-specific memory CD8 + T cells were transferred into non-immunized animals, they showed higher rates of proliferation in the bone marrow than in the spleen and lymph nodes 3,10 . In general, the data concerning memory CD8 + T cell cycling in the bone marrow are all in agreement. However, memory CD4 + T cell proliferation requires further investigation, as antigen-specific cells have not been examined in the bone marrow 11 .Despite the apparent consistency of the data concerning memory CD8 + T cells, their interpretations differ. Radbruch's group proposes that these data suggest similarity between bone marrow memory CD8 + T cells and peripheral...

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GITR-Dependent Regulation of 4-1BB Expression: Implications for T Cell Memory and Anti–4-1BB–Induced Pathology

Cited by 36 publications

References 53 publications

Corticosterone Signaling in Central Memory CD8+ T Cells Triggers Apoptosis that is Inhibited by Interleukin-15

Corticosterone Signaling in Central Memory CD8+ T Cells Triggers Apoptosis that is Inhibited by Interleukin-15

Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC

Maintenance of memory T cells in the bone marrow: survival or homeostatic proliferation?

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