The influence of CD95L expression on tumor rejection in mice

Igney, Frederik H.; Behrens, Christian K.; Krammer, Peter H.

doi:10.1002/eji.200324176

Cited by 13 publications

(16 citation statements)

References 47 publications

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“…Previous reports using magnetic bead-isolated CD4 ϩ CD25 ϩ T cells showed CD95 expression on human and murine CD25 ϩ cells (7,16). We confirmed these data on CD4 ϩ T reg FACSsorted for very high CD25 expression.…”

Section: Cd4supporting

confidence: 89%

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Cutting Edge: In Contrast to Effector T Cells, CD4+CD25+FoxP3+ Regulatory T Cells Are Highly Susceptible to CD95 Ligand- but Not to TCR-Mediated Cell Death

Fritzsching

Oberle

Eberhardt

et al. 2005

The Journal of Immunology

155

177

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CD4+CD25+FoxP3+ regulatory T cells (Treg) suppress T cell function and protect rodents from autoimmune disease. Regulation of Treg during an immune response is of major importance. Enhanced survival of Treg is beneficial in autoimmune disease, whereas increased depletion by apoptosis is advantageous in cancer. We show here that freshly isolated FACS-sorted Treg are highly sensitive toward CD95-mediated apoptosis, whereas other T cell populations are resistant to CD95-induced apoptosis shortly after isolation. In contrast, TCR restimulation of Treg in vitro revealed a reduced sensitivity toward activation-induced cell death compared with CD4+CD25− T cells. Thus, the apoptosis phenotype of Treg is unique in comparison to other T cells, and this might be further explored for novel therapeutic modulations of Treg.

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Section: Cd4supporting

confidence: 89%

“…CD95L was produced as a leucine zipper-tagged ligand of CD95 (15,16). The anti-CD3 Ab OKT3 and the agonistic monoclonal anti-CD95 Ab (anti-Apo-1) were purified from hybdridoma supernatants by protein A affinity purification (15 …”

Section: Abs and Reagentsmentioning

confidence: 99%

Cutting Edge: In Contrast to Effector T Cells, CD4+CD25+FoxP3+ Regulatory T Cells Are Highly Susceptible to CD95 Ligand- but Not to TCR-Mediated Cell Death

Fritzsching

Oberle

Eberhardt

et al. 2005

The Journal of Immunology

155

177

View full text Add to dashboard Cite

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“…Current evidence for the role of Fas/FasL-mediated apoptosis in T suppressor homeostasis is inconclusive. Although T suppressor cells express Fas constitutively (39,40), they are resistant to anti-Fas Ab-mediated apoptosis (41). In contrast, it was recently reported that whereas CD4 ϩ CD25 ϩ T suppressors were resistant to AICD via TCR-stimulation, they were uniquely sensitive to soluble CD95 ligand-mediated apoptosis in vitro (42).…”

Section: Cd25mentioning

confidence: 99%

Reversing Tumor Immune Suppression with Intratumoral IL-12: Activation of Tumor-Associated T Effector/Memory Cells, Induction of T Suppressor Apoptosis, and Infiltration of CD8+ T Effectors

Kilinc

Aulakh

Nair

et al. 2006

The Journal of Immunology

118

129

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A single intratumoral injection of IL-12 and GM-CSF-loaded slow-release microspheres induces T cell-dependent eradication of established primary and metastatic tumors in a murine lung tumor model. To determine how the delivery of cytokines directly to the microenvironment of a tumor nodule induces local and systemic antitumor T cell activity, we characterized therapy-induced phenotypic and functional changes in tumor-infiltrating T cell populations. Analysis of pretherapy tumors demonstrated that advanced primary tumors were infiltrated by CD4+ and CD8+ T cells with an effector/memory phenotype and CD4+CD25+Foxp3+ T suppressor cells. Tumor-associated effector memory CD8+ T cells displayed impaired cytotoxic function, whereas CD4+CD25+Foxp3+ cells effectively inhibited T cell proliferation demonstrating functional integrity. IL-12/GM-CSF treatment promoted a rapid up-regulation of CD43 and CD69 on CD8+ effector/memory T cells, augmented their ability to produce IFN-γ, and restored granzyme B expression. Importantly, treatment also induced a concomitant and progressive loss of T suppressors from the tumor. Further analysis established that activation of pre-existing effector memory T cells was short-lived and that both the effector/memory and the suppressor T cells became apoptotic within 4 days of treatment. Apoptotic death of pre-existing effector/memory and suppressor T cells was followed by infiltration of the tumor with activated, nonapoptotic CD8+ effector T lymphocytes on day 7 posttherapy. Both CD8+ T cell activation and T suppressor cell purge were mediated primarily by IL-12 and required IFN-γ. This study provides important insight into how local IL-12 therapy alters the immunosuppressive tumor milieu to one that is immunologically active, ultimately resulting in tumor regression.

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“…For apoptosis induction, T cells were stimulated with a 1:10 dilution of a leucine zipper-tagged CD95 ligand (CD95L). 17,18 Annexin V Alexa Fluor 488 was purchased from Molecular Probes (Eugene, OR, USA) and propidium iodide (PI) was obtained from Sigma-Aldrich (St Louis, MO, USA). Unstimulated cells were incubated with CD95L-free control medium yielding spontaneous apoptosis of 15-30% in 20 h. Cell death was assessed by annexin V/PI costaining and forward-to-sideward-scatter profile.…”

Section: Cell Isolation and Sortingmentioning

confidence: 99%

Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas

et al. 2006

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Cutaneous T-cell lymphomas (CTCL) are mainly comprised of two variants: mycosis fungoides (MF) with CD4 þ tumor cells confined to the skin and the leukemic Sé zary syndrome with tumor cell spread to the blood. In this study, we investigated cutaneous expression of the regulatory T-cell (T reg ) marker FOXP3 in 30 CTCL patients. Immunohistochemical analysis revealed significantly lower numbers of CD4 þ FOXP3 þ cells within the dermal lymphomononuclear infiltrate of Sé zary patients (16% FOXP3 þ cells of CD4 þ cells) in contrast to MF (43% FOXP3 þ cells (Po0.05)) and rare types of CTCL (45% FOXP3 þ cells). Furthermore, CD4 þ FOXP3 þ T cells were also markedly reduced in the CD4 þ population within the peripheral blood of Sé zary patients compared to controls as determined by fluorescence-activated cell sorter, quantitative PCR and functional analyses. The data support the conclusion that the neoplastic cells in CTCL do not express the T reg marker FOXP3. Our data also identify Sé zary syndrome as, to our knowledge, the first reported neoplastic disease with a clear reduction in T reg numbers within the CD4 þ population. This lack of T reg might account for the more aggressive nature of Sé zary syndrome compared with other CTCL.

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The influence of CD95L expression on tumor rejection in mice

Cited by 13 publications

References 47 publications

Cutting Edge: In Contrast to Effector T Cells, CD4+CD25+FoxP3+ Regulatory T Cells Are Highly Susceptible to CD95 Ligand- but Not to TCR-Mediated Cell Death

Cutting Edge: In Contrast to Effector T Cells, CD4+CD25+FoxP3+ Regulatory T Cells Are Highly Susceptible to CD95 Ligand- but Not to TCR-Mediated Cell Death

Reversing Tumor Immune Suppression with Intratumoral IL-12: Activation of Tumor-Associated T Effector/Memory Cells, Induction of T Suppressor Apoptosis, and Infiltration of CD8+ T Effectors

Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas

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