Interleukin-4-mediated downregulation of cytotoxic T lymphocyte activity is associated with reduced proliferation of antigen-specific CD8+ T cells

Rolph, Michael S.; Ramshaw, Ian A.

doi:10.1016/s1286-4579(03)00190-4

Cited by 14 publications

(10 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some work in which IL-4 has been ablated by gene targeting or delivered exogenously, for example using recombinant viruses, indicated that IL-4 reduced CTL activity and/or viral clearance (7)(8)(9)(10)(11)(12)(13)(14)(15). Adoptive transfer of type 1-or 2-polarized CD8 ϩ T cells (termed Tc1 or Tc2, respectively) also showed that IL-4-producing Tc2 cells were less efficient than Tc1 cells in tumor rejection (16 -18).…”

Section: N Aive Cd8mentioning

confidence: 99%

Progressive Differentiation and Commitment of CD8+ T Cells to a Poorly Cytolytic CD8low Phenotype in the Presence of IL-4

Kienzle

Olver

Buttigieg

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

Exposure to IL-4 during activation of naive murine CD8+ T cells leads to generation of IL-4-producing effector cells with reduced surface CD8, low perforin, granzyme B and granzyme C mRNA, and poor cytolytic function. We show in this study that maximal development of these cells depended on exposure to IL-4 for the first 5 days of activation. Although IL-4 was not required at later times, CD8 T cell clones continued to lose surface CD8 expression with prolonged culture, suggesting commitment to the CD8low phenotype. This state was reversible in early differentiation. When single CD8low cells from 4-day cultures were cultured without IL-4, 65% gave rise to clones that partly or wholly comprised CD8high cells; the proportion of reverted clones was reduced or increased when the cells were cloned in the presence of IL-4 or anti-IL-4 Ab, respectively. CD8 expression positively correlated with perforin and granzyme A, B, and C mRNA, and negatively correlated with IL-4 mRNA levels among these clones. By contrast, most CD8low cells isolated at later time points maintained their phenotype, produced IL-4, and exhibited poor cytolytic function after many weeks in the absence of exogenous IL-4. We conclude that IL-4-dependent down-regulation of CD8 is associated with progressive differentiation and commitment to yield IL-4-producing cells with little cytolytic activity. These data suggest that the CD4−CD8− cells identified in some disease states may be the product of a previously unrecognized pathway of effector differentiation from conventional CD8+ T cells.

show abstract

Section: N Aive Cd8mentioning

confidence: 99%

Progressive Differentiation and Commitment of CD8+ T Cells to a Poorly Cytolytic CD8low Phenotype in the Presence of IL-4

Kienzle

Olver

Buttigieg

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…IL-4 expression reduces the OVA peptide-specific CTL response significantly and is associated with a decrease in the proliferation of OVA-specific CTLs. However, on a per cell basis, the production of IFN-g and the cytotoxicity of OVAspecific CTL cells are not affected [28]. This would indicate that the reduction in CTL responses caused by IL-4 is due to the reduced numbers of antigen-specific effector cells as opposed to the downregulation of the effector functions of these cells.…”

Section: Vaccinia Virus Expressing Il-4mentioning

confidence: 96%

“…One elegant study examined the effect of IL-4 expression by VACV on the CTL response, using a TCR transgenic system [28]. Transgenic H-2K b mice specific for ovalbumin (OVA) peptide were immunized with either VACV-OVA or VACV-OVA-IL-4 [19,28].…”

Section: Vaccinia Virus Expressing Il-4mentioning

confidence: 99%

See 1 more Smart Citation

The ‘supervirus’? Lessons from IL-4-expressing poxviruses

Stanford¹,

McFadden²

2005

Trends in Immunology

View full text Add to dashboard Cite

“…Ectromelia virus expressing IL-4 was able to break immunity induced by previous infection, a finding not shown in either the MV-IL-4 or vaccinia virus-IL-4 studies. This increased pathogenicity is due to the ability of IL-4 to dampen Th1-type immune processes, particularly IL-12, IL-2, and gamma interferon (1,16,27). In contrast, the expression of Th1 cytokines has been hypothesized to result in an attenuated infection, bolstered by a stronger type 1 immune response.…”

mentioning

confidence: 99%

Myxoma Virus Expressing Human Interleukin-12 Does Not Induce Myxomatosis in European Rabbits

Stanford

Barrett

Gilbert

et al. 2007

J Virol

View full text Add to dashboard Cite

Myxoma virus (MV) is a candidate for oncolytic virotherapy due to its ability to selectively infect and kill tumor cells, yet MV is a species-specific pathogen that causes disease only in European rabbits. To assess the ability of MV to deliver cytokines to tumors, we created an MV (vMyxIL-12) that expresses human interleukin-12 (IL-12). vMyxIL-12 replicates similarly to wild-type MV, and virus-infected cells secrete bioactive IL-12. Yet, vMyxIL-12 does not cause myxomatosis, despite expressing the complete repertoire of MV proteins. Thus, vMyxIL-12 exhibits promise as an oncolytic candidate and is safe in all known vertebrate hosts, including lagomorphs.Myxoma virus (MV) is a poxvirus and the prototypic member of the Leporipoxvirus genus. MV is the causative agent of myxomatosis, a lethal and deblilitating disease of European rabbits (Oryctolagus cuniculus), characterized by profound systemic immunosuppression (11,12). MV has been completely sequenced (5), and many virus-encoded immunomodulatory proteins have been identified (2,20,32,41). A significant number of individual MV genes have been genetically removed, and the effect on the ability of the knockout virus to cause mxyomatosis has been evaluated (18,19). Ablation of some viral genes had minor effects on the ability of the virus to cause disease in rabbits, while others were attenuated to the point that the virus no longer causes significant pathology. These studies, combined with concomitant in vitro analysis of the individual viral gene products, have provided many insights into the mechanism by which MV causes disease in rabbits (20,32).Although MV cannot cause disease in any vertebrate species other than lagomorphs, it has been demonstrated that MV can preferentially infect and kill human cancer cells (33). This has led to studies examining MV as a virotherapeutic for human cancer. The ability of MV to infect and clear tumors in vivo has been demonstrated in a model for human glioblastoma, where intratumoral injection of MV effectively "cured" human gliomas in immunocompromised mice (23). The ability of MV to infect human tumor cells has been linked to activity of cellular Akt kinase (36), and drugs that act on this host signaling pathway have been shown to augment MV infection (30).To stimulate an anticancer immune response within a largely nonresponsive tumor microenvironment, cytokine therapy has been employed. Interleukin-12 (IL-12) is produced by antigenpresenting cells (29) and acts as an important mediator of T-cell responses through promoting T type 1 immunity (15).IL-12 exhibits significant antitumor effects in both animal models and human patients, yet the toxicity induced by systemic administration prevented further use clinically (15,22,26,28,34,35,37). Thus, local dosing of IL-12 within tumors has been explored. IL-12 has been delivered to murine (14) and human (4) tumors using IL-12 encapsulated microspheres (14) or irradiated tumor cells transfected with an IL-12 expression plasmid (13). Viral vectors, including herpesvirus (3, 38-40) a...

show abstract

Interleukin-4-mediated downregulation of cytotoxic T lymphocyte activity is associated with reduced proliferation of antigen-specific CD8+ T cells

Cited by 14 publications

References 66 publications

Progressive Differentiation and Commitment of CD8+ T Cells to a Poorly Cytolytic CD8low Phenotype in the Presence of IL-4

Progressive Differentiation and Commitment of CD8+ T Cells to a Poorly Cytolytic CD8low Phenotype in the Presence of IL-4

The ‘supervirus’? Lessons from IL-4-expressing poxviruses

Myxoma Virus Expressing Human Interleukin-12 Does Not Induce Myxomatosis in European Rabbits

Contact Info

Product

Resources

About