Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time dependent

Zhang, Benyue; Maris, Charles H.; Foell, Juergen; Whitmire, Jason K.; Niu, Liguo; Song, Jing; Kwon, Byoung S.; Vella, Anthony T.; Ahmed, Rafi; Jacob, Joshy; Mittler, Robert S.

doi:10.1172/jci32426

Cited by 51 publications

(63 citation statements)

References 43 publications

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“…During murine CMV infection, 4-1BB suppresses CD8 T cell responses against acute epitopes, but enhances CD8 T cell responses during the latent phase (43). Supporting this study, agonistic anti-4-1BB Abs improve or impair T cell responses against acute infection with LCMV and influenza depending on the time of application (44). Similar to CD27, 4-1BB required Fasdriven apoptosis to induce contraction of CD8 T cell responses (44).…”

Section: Discussionmentioning

confidence: 67%

“…Supporting this study, agonistic anti-4-1BB Abs improve or impair T cell responses against acute infection with LCMV and influenza depending on the time of application (44). Similar to CD27, 4-1BB required Fasdriven apoptosis to induce contraction of CD8 T cell responses (44). The costimulatory pathway through CD28 has not been reported to downregulate T cell responses by itself but is counteracted by the inhibitory family member CTLA4 that also binds B7 molecules (45).…”

Section: Discussionmentioning

confidence: 84%

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CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

Wensveen

Unger

Kragten

et al. 2012

The Journal of Immunology

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Apoptosis plays an essential role in the removal of activated CD8 T cells that are no longer required during or postinfection. The Bim-dependent intrinsic pathway of apoptosis removes effector CD8 T cells upon clearance of viral infection, which is driven by withdrawal of growth factors. Binding of Fas ligand to Fas mediates activation-induced T cell death in vitro and cooperates with Bim to eliminate CD8 T cells during chronic infection in vivo, but it is less clear how this pathway of apoptosis is initiated. In this study, we show that the costimulatory TNFR CD27 provides a dual trigger that can enhance survival of CD8 T cells, but also removal of activated CD8 T cells through Fas-driven apoptosis. Using in vitro stimulation assays of murine T cells with cognate peptide, we show that CD27 increases T cell survival after stimulation with low doses of Ag, whereas CD27 induces Fas-driven T cell apoptosis after stimulation with high doses of Ag. In vivo, the impact of constitutive CD70-driven stimulation on the accumulation of memory and effector CD8 T cells is limited by Fas-driven apoptosis. Furthermore, introduction of CD70 signaling during acute infection with influenza virus induces Fas-dependent elimination of influenza-specific CD8 T cells. These findings suggest that CD27 suppresses its costimulatory effects on T cell survival through activation of Fas-driven T cell apoptosis to maintain T cell homeostasis during infection.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 84%

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

Wensveen

Unger

Kragten

et al. 2012

The Journal of Immunology

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“…Anti-4-1BB Abs can enhance CD8 T cell responses to viruses (20,21,57), and a single dose of anti-4-1BB Ab can completely correct the CD8 memory defect in 4-1BBL-deficient mice in a nonlethal influenza model (20). However, attempts to correct the defect in response to severe influenza in 4-1BBL-deficient mice by systemic administration of anti-4-1BB agonistic Abs were unsuccessful, and resulted in accelerated disease (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Endogenous 4-1BB Ligand Plays a Critical Role in Protection from Influenza-Induced Disease

Lin

Sedgmen

Moraes

et al. 2009

The Journal of Immunology

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A critical issue during severe respiratory infection is whether it is the virus or the host response that does the most damage. In this study, we show that endogenous 4-1BBL plays a critical role in protecting mice from severe effects of influenza disease. During mild respiratory influenza infection in which virus is rapidly cleared, the inducible costimulatory receptor 4-1BB is only transiently induced on lung T cells and 4-1BB ligand (4-1BBL) is completely dispensable for the initial CD8 T cell response and mouse survival. In contrast, during more severe respiratory influenza infection with prolonged viral load, 4-1BB expression on lung CD8 T cells is sustained, and 4-1BBL-deficient mice show decreased CD8 T cell accumulation in the lungs, decreased viral clearance, impaired lung function, and increased mortality. Transfer of an optimal number of naive Ag-specific T cells before infection protects wild-type but not 4-1BBL-deficient mice from an otherwise lethal dose of influenza virus. T he CD8 T cells are important mediators of protective immunity to viruses (1). Indeed a strong CD8 T cell response to influenza offers the hope of cross-protective immunity to diverse influenza strains (2, 3). However, there is a concern that too strong an immune response in the lung will cause immune pathology and a worse outcome (4 -6). Upon initial encounter with Ag, T cells commit to programmed expansion, which occurs independently of the continued presence of Ag (7,8). How then does the immune system provide the appropriate level of T cell stimulation for a particular infection? T cells regulate their level of response by integrating signals from the Ag-specific receptor as well as from costimulatory, coinhibitory, and cytokine receptors which in turn influence the initiation, duration, and differentiation of the response (9 -12). The initial activation of T cells requires costimulatory signals from CD28, expressed on resting T cells. In addition, during an on-going immune response, other costimulatory receptors and ligands are up-regulated on the T cells and APCs (13-15). The question arises as to why so many costimulatory receptor ligand pairs have accumulated in the mammalian immune system. Here we provide evidence that the expression of one such costimulatory receptor, 4-1BB, is sustained in response to severe as compared with mild respiratory infection with influenza virus, thereby allowing the immune system to maintain a level of CD8 T cell response appropriate for the severity of the infection.The receptor 4-1BB (CD137) is a member of the TNFR family expressed on Ag-receptor activated T cells (14, 16 -18). In vivo with nonreplicating immunogens, 4-1BB is rapidly and transiently up-regulated on T cells upon immunization, before the first cell division and concomitantly with the expression of the early activation marker CD69 (19). Evidence that 4-1BB can play a role early in the response comes from systemic administration of agonist anti-4-1BB Abs, which can enhance initial antitumor and antiviral T cell responses wi...

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“…Recently, Zhang et al [38] have reported studies in lymphocytic choriomeningitis virus-infected mice, which show that, depending on the timing of treatment, anti-4-1BB mAb can either cause activation-induced cell death or enhance anti-viral immunity. When given early post-infection, anti-4-1BB was immunosuppressive, with depletion of virus-specific CD81 T cells.…”

Section: Discussionmentioning

confidence: 99%

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

et al. 2008

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Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. In particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD81 T cells but produced fewer IFN-c-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.

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Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time dependent

Cited by 51 publications

References 43 publications

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

Endogenous 4-1BB Ligand Plays a Critical Role in Protection from Influenza-Induced Disease

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

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