Lymphotoxin α−/− Mice Develop Functionally Impaired CD8+ T Cell Responses and Fail to Contain Virus Infection of the Central Nervous System

Kumaraguru, Udayasankar; Davis, Ila A.; Deshpande, Shilpa; Tevethia, Satvir S.; Rouse, Barry T.

doi:10.4049/jimmunol.166.2.1066

Cited by 70 publications

(49 citation statements)

References 34 publications

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“…1). Recent reports describing an association between disruption of mlT and defects in host immunity have linked this effect to impaired function of CD8 ϩ T cells (15,17). Thus, we hypothesized that the rejection observed in LT␣ Ϫ/Ϫ mice was mediated by CD4 ϩ T cells.…”

Section: Resultsmentioning

confidence: 99%

“…The binding of mlT expressed by T cells and activated B cells to lymphotoxin ␤ receptor (LT␤R) expressed on stromal cells and cells of monocytic origin has been shown to be critical for the development of lymphoid organs (13) and for the regulation of chemokine production (14). Disruption of these molecular interactions has been reported to impair the immune response to viruses and tumors (15)(16)(17)(18)(19).…”

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confidence: 99%

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Cutting Edge: Membrane Lymphotoxin Regulates CD8+ T Cell-Mediated Intestinal Allograft Rejection

Guo

Wang

Meng³

et al. 2001

The Journal of Immunology

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Blocking the CD28/B7 and/or CD154/CD40 costimulatory pathways promotes long-term allograft survival in many transplant models where CD4+ T cells are necessary for rejection. When CD8+ T cells are sufficient to mediate rejection, these approaches fail, resulting in costimulation blockade-resistant rejection. To address this problem we examined the role of lymphotoxin-related molecules in CD8+ T cell-mediated rejection of murine intestinal allografts. Targeting membrane lymphotoxin by means of a fusion protein, mAb, or genetic mutation inhibited rejection of intestinal allografts by CD8+ T cells. This effect was associated with decreased monokine induced by IFN-γ (Mig) and secondary lymphoid chemokine (SLC) gene expression within allografts and spleens respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4+ T cells. Combining disruption of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice. These data demonstrate that membrane lymphotoxin is an important regulatory molecule for CD8+ T cells mediating rejection and suggest a strategy to avoid costimulation blockade-resistant rejection.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Cutting Edge: Membrane Lymphotoxin Regulates CD8+ T Cell-Mediated Intestinal Allograft Rejection

Guo

Wang

Meng³

et al. 2001

The Journal of Immunology

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“…This result reinforces the conclusion that TNF-mediated protection against HSV-1-induced mortality is independent of signaling via the known TNF receptors, p55 and p75. Although the monomeric sTNFR1 preparation used does not bind LT when tested in vitro, there is a remote possibility that in vivo it might bind LT in addition to TNF, both of which are natural ligands for p55 that have been implicated in the mediation of resistance to HSV-1 (8,24,39). Consequently, we also tested an anti-TNF monoclonal antibody (MAb) that does not bind LT and demonstrated that mortality due to HSE was increased to an extent similar to that observed with sTNFR1 treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Tumor Necrosis Factor (TNF) Protects Resistant C57BL/6 Mice against Herpes Simplex Virus-Induced Encephalitis Independently of Signaling via TNF Receptor 1 or 2

Lundberg¹,

Welander²,

Edwards

et al. 2007

J Virol

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Tumor necrosis factor (TNF) is a multifunctional cytokine that has a role in induction and regulation of host innate and adaptive immune responses. The importance of TNF antiviral mechanisms is reflected by the diverse strategies adopted by different viruses, particularly members of the herpesvirus family, to block TNF responses. TNF binds and signals through two receptors, Tnfrsf1a (TNF receptor 1 [TNFR1], or p55) and Tnfrsf1b (TNFR2, or p75). We report here that herpes simplex virus 1 (HSV-1) infection of TNF ؊/؊ mice on the resistant C57BL/6 genetic background results in significantly increased susceptibility (P < 0.0001, log rank test) to fatal HSV encephalitis (HSE) and prolonged persistence of elevated levels of virus in neural tissues. In contrast, although virus titers in neural tissues of p55 ؊/؊ N13 mice were elevated to levels comparable to what was found for the TNF ؊/؊ mice, the p55 ؊/؊ N13 mice were as resistant as control C57BL/6 mice (P > 0.05). The incidence of fatal HSE was significantly increased by in vivo neutralization of TNF using soluble TNFR1 (sTNFR1) or depletion of macrophages in C57BL/6 mice (P ‫؍‬ 0.0038 and P ‫؍‬ 0.0071, respectively). Strikingly, in vivo neutralization of TNF in HSV-1-infected p55 ؊/؊ p75 ؊/؊ mice by use of three independent approaches (treatment with soluble p55 receptor, anti-TNF monoclonal antibody, or in vivo small interfering RNA against TNF) resulted in significantly increased mortality rates (P ‫؍‬ 0.005), comparable in magnitude to those for C57BL/6 mice treated with sTNFR1 (P ‫؍‬ 0.0018). Overall, these results indicate that while TNF is required for resistance to fatal HSE, both p55 and p75 receptors are dispensable. Precisely how TNF mediates protection against HSV-1 mortality in p55 ؊/؊ p75 ؊/؊ mice remains to be determined.Early innate and subsequent adaptive immune responses to viral and bacterial pathogens are critically dependent on the tumor necrosis factor (TNF) superfamily of cytokines. These TNF superfamily cytokines act as effectors of host defense and regulate peripheral lymphoid tissue organogenesis and differentiation of natural killer cells and lymphoid cells (42,46). TNF, a multifunctional cytokine produced primarily by activated macrophages (70), functions as a key regulator of leukocyte trafficking by affecting chemokine expression and stimulating antigen presentation, which it does by inducing dendritic cell maturation (26, 58). TNF exists in two forms, a precursor 26-kDa membrane-bound form (mTNF) and a 17-kDa soluble form (sTNF), both of which are bioactive (46, 71). TNF and the closely related ligand lymphotoxin-␣ (LT) bind as homotrimers to two receptors, TNF receptor 1 (TNFR1, or p55) and TNFR2 (p75), which are widely expressed on most cell types (71). Activation of p55 generally results in gene activation that leads to induction of inflammatory and cytotoxic responses, while activation of TNFR2 is associated with thymocyte proliferation and T-cell activation. In response to TNF binding, lipopolysaccharide (LPS) and several other s...

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“…The CTL assay was performed as described earlier (21). Briefly, effector cells generated after in vitro expansion (with peptide or HSV) were analyzed for their ability to kill MHC-matched Ag-presenting targets.…”

Section: Ctl Assaysmentioning

confidence: 99%

“…The targets included 51 Cr-pulsed, MHC-matched, and HSV-infected (EMT6-HSV), MHC-matched and DYATLGVGV-pulsed (EMT6-DYATL GVGV), MHC-mismatched, HSV-infected, and DYATLGVGV-pulsed (MC38-HSV and MC38-DYATLGVGV), and MHC-matched uninfected or unpulsed (EMT6) targets. The chromium release results were computed and are expressed as lytic units as described elsewhere (21).…”

Section: Ctl Assaysmentioning

confidence: 99%

Concomitant Helper Response Rescues Otherwise Low Avidity CD8+ Memory CTLs to Become Efficient Effectors In Vivo

Kumaraguru

Suvas

Biswas

et al. 2004

The Journal of Immunology

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This report seeks a means of maximizing memory CD8 T cell responses to peptide immunization. Delivery of the CD8 peptide epitope by stress protein, heat shock protein (hsp)70, results in excellent immunogenicity at the acute phase but memory responses were poor both in terms of the number of responding cells as well as their functional avidity. We demonstrate for the first time that hsp70 can also be used as a vehicle to achieve CD4 T cell responses to loaded peptide epitopes and that coimmunization with hsp70 loaded with both CD8 and CD4 peptide epitopes may increase memory up to 3-fold. Furthermore, CD8+ T cell memory responses were of higher avidity measured both by in vitro cytotoxicity assays and a new methodology that measures the avidity of CTL activity in vivo in mice. Our results emphasize that peptide immunization remains a viable approach to induce long-term CD8+ T cell function, providing steps are taken to assure appropriate stimulation of Th cell responses.

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Lymphotoxin α−/− Mice Develop Functionally Impaired CD8+ T Cell Responses and Fail to Contain Virus Infection of the Central Nervous System

Cited by 70 publications

References 34 publications

Cutting Edge: Membrane Lymphotoxin Regulates CD8+ T Cell-Mediated Intestinal Allograft Rejection

Cutting Edge: Membrane Lymphotoxin Regulates CD8+ T Cell-Mediated Intestinal Allograft Rejection

Tumor Necrosis Factor (TNF) Protects Resistant C57BL/6 Mice against Herpes Simplex Virus-Induced Encephalitis Independently of Signaling via TNF Receptor 1 or 2

Concomitant Helper Response Rescues Otherwise Low Avidity CD8+ Memory CTLs to Become Efficient Effectors In Vivo

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