4-1BB Promotes the Survival of CD8+ T Lymphocytes by Increasing Expression of Bcl-xL and Bfl-1

Lee, Hyeon‐Woo; Park, Su-Jung; Choi, Beom K.; Kim, Hyun Hwa; Nam, Kyung-Ok; Kwon, Byoung S.

doi:10.4049/jimmunol.169.9.4882

Cited by 323 publications

(276 citation statements)

References 23 publications

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“…Importantly, both receptors are expressed on CD8 1 T cells following TCR signalling and appear to have similar roles in activation [31] with agonistic mAb directly enhancing CD8 1 T-cell responses, largely through improved survival of antigen-activated T cells [30,41]. Both 4-1BB and OX40 interact with common TRAF proteins, activate NFkB pathways and induce expression of anti-apoptotic Bcl-2 family molecules [42][43][44]. Such overlap might suggest some redundancy in function, with consequently less potential for synergy, although deficiencies in either 4-1BB or OX40 on CD8 1 T cells result in impaired T-cell responses [15], indicating that signalling through both is necessary for optimal function.…”

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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“…4-1BBL is expressed on activated antigen presenting cells [234]. 4-1BB signal also induces the anti-apoptotic proteins Bcl-x L and A1/Bfl-1 in T lymphocytes through an NF-κB dependent pathway [238][239][240]. However, during viral infection, CD4 + T cell function is unimpaired in 4-1BB -/-mice.…”

Section: Costimulatory Molecules and Anti-apoptotic Molecules In T Cellsmentioning

confidence: 99%

The role of apoptosis in the development and function of T lymphocytes

et al. 2005

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Apoptosis plays an essential role in T cell biology. Thymocytes expressing nonfunctional or autoreactive TCRs are eliminated by apoptosis during development. Apoptosis also leads to the deletion of expanded effector T cells during immune responses. The dysregulation of apoptosis in the immune system results in autoimmunity, tumorogenesis and immunodeficiency. Two major pathways lead to apoptosis: the intrinsic cell death pathway controlled by Bcl-2 family members and the extrinsic cell death pathway controlled by death receptor signaling. These two pathways work together to regulate T lymphocyte development and function.

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“…Extensive evidence supports the role of 4-1BB as a costimulatory molecule that can function independently of CD28 [9,13,14] to activate T cells [10,15,16]. 4-1BB can influence cytokine production, proliferation and survival of T cells in vitro and in vivo [8][9][10][16][17][18][19][20][21][22][23][24]. Stimulatory anti-4-1BB antibodies show a preferential role for 4-1BB in CD8 + T cell activation in vitro [20].…”

Section: Introductionmentioning

confidence: 99%

Expression and function of 4‐1BB during CD4 versus CD8 T cell responses in vivo

Dawicki

Watts

2004

Eur J Immunol

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4-1BBL -/-mice have a defect in recall CD8 + T cell responses to viruses, whereas CD4 + T cell responses to virus are unimpaired in these mice. In contrast, both CD4 + and CD8 + T cells respond to 4-1BB ligand (4-1BBL) in vitro. To clarify the role of 4-1BB/4-1BBL in CD4 + versus CD8 + T cell responses in vivo, we compared CD4 (OT-II) and CD8 (OT-I) TCR transgenic T cells responding to the same antigen in an in vivo adoptive transfer model in 4-1BBL +/+ versus 4-1BBL -/-mice. During primary and secondary responses, expression of 4-1BB on in vivo-activated TCR transgenic T cells was earlier and more transient than previously observed in vitro, correlating with expression of the early activation antigen CD69 and preceding the transition to the CD44 hi state. Although 4-1BB is expressed early in the primary response, there was no effect of 4-1BBL deficiency on initial CD8 T cell expansion and only a minor effect on initial CD4 T cell expansion. The major effect of 4-1BB/4-1BBL interaction is on the T cell recall response. This is due to effects of 4-1BBL on maintenance of T cell numbers at the end of the primary response with additional effects of 4-1BBL on secondary expansion of T cells.

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4-1BB Promotes the Survival of CD8+ T Lymphocytes by Increasing Expression of Bcl-xL and Bfl-1

Cited by 323 publications

References 23 publications

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

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

The role of apoptosis in the development and function of T lymphocytes

Expression and function of 4‐1BB during CD4 versus CD8 T cell responses in vivo

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