CD47high Expression on CD4 Effectors Identifies Functional Long-Lived Memory T Cell Progenitors

Van, Vu Quang; Raymond, Marianne; Baba, Nobuyasu; Rubio, Manuel; Wakahara, Keiko; Susin, Santos A.; Sarfati, Marika

doi:10.4049/jimmunol.1102702

Cited by 23 publications

(28 citation statements)

References 36 publications

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“…Interestingly, in rats and mice, CD47 has been implicated in myelin phagocytosis through modulation of CD47:SIRP-α interactions (134) This is an immune evasion pathway that may have been exploited by DFT1, which originated from a Schwann cell and expresses high levels of myelin (37). Despite the nearly ubiquitous expression of CD47 by all cell types, expression levels are highly variable and can be modulated by inflammation (135, 136). High levels of CD47 found on many types of human cancer, including leukemia (137–139), lymphoma (140), and several types of solid tumor cancers (141, 142) and are often associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to facilitating cancer cell immune evasion, CD47 also affects T cell and NK cell homeostasis (147, 148). CD47 is suggested to facilitate longevity by reducing clearance by phagocytes (135). Blockade of CD47 could thus decrease memory cell longevity and increase turnover of T cells and NK cells and could be detrimental to long-term DFT immunity in wild devils that could be re-exposed to DFT.…”

Section: Discussionmentioning

confidence: 99%

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Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

et al. 2017

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Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii) facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs) in genes and protein domains that have not been previously reported in any species. This checkpoint molecule analysis and review of salient features for each of the molecules presented here can serve as road map for the development of a Tasmanian devil facial tumor disease immunotherapy. Finally, the strategies can be used as a guide for veterinarians, ecologists, and other researchers willing to venture into the nascent field of wild immunology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

et al. 2017

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“…However, CD47 expression on T cells is well known to regulate their activation and functional differentiation in vitro and in vivo (21, 43). Our results show for the first time that blocking CD47 in effector cytotoxic T cells can directly enhance their anti-tumor response.…”

Section: Discussionmentioning

confidence: 99%

CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

et al. 2014

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While significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here we report that CD47 blockade directly enhances tumor immunosurveillance by CD8+ T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8+ T cells restored combinatorial efficacy. Further, ablation of CD8+ T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8+ CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8+ T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8+ T cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8+ cytotoxic T cells, with the potential to increase curative responses.

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“…CD47 is a broadly expressed protein that is often tightly associated with integrins (27). CD47 cell-surface expression on T cells is regulated during activation (28,29) and delivers a positive signal during encounters with cognate Ag (30,31). We asked whether the observed differential binding of NOD versus NOR SIRPa to mCD47 impacted T cell-APC interaction and T cell activation and proliferation.…”

Section: Sirpa Variation On DC Impacts T Cell Proliferation and Transmentioning

confidence: 99%

Polymorphism in the Innate Immune Receptor SIRPα Controls CD47 Binding and Autoimmunity in the Nonobese Diabetic Mouse

Wong

Mortin-Toth

Sung

et al. 2014

The Journal of Immunology

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The signal regulatory protein (SIRP) locus encodes a family of paired receptors that mediate both activating and inhibitory signals and is associated with type 1 diabetes (T1D) risk. The NOD mouse model recapitulates multiple features of human T1D and enables mechanistic analysis of the impact of genetic variations on disease. In this study, we identify Sirpa encoding an inhibitory receptor on myeloid cells as a gene in the insulin-dependent diabetes locus 13.2 (Idd13.2) that drives islet inflammation and T1D. Compared to T1D-resistant strains, the NOD variant of SIRPα displayed greater binding to its ligand CD47, as well as enhanced T cell proliferation and diabetogenic potency. Myeloid cell–restricted expression of a Sirpa transgene accelerated disease in a dose-dependent manner and displayed genetic and functional interaction with the Idd5 locus to potentiate insulitis progression. Our study demonstrates that variations in both SIRPα sequence and expression level modulate T1D immunopathogenesis. Thus, we identify Sirpa as a T1D risk gene and provide insight into the complex mechanisms by which disease-associated variants act in concert to drive defined stages in disease progression.

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CD47high Expression on CD4 Effectors Identifies Functional Long-Lived Memory T Cell Progenitors

Cited by 23 publications

References 36 publications

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

Polymorphism in the Innate Immune Receptor SIRPα Controls CD47 Binding and Autoimmunity in the Nonobese Diabetic Mouse

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