Signaling through the Inhibitory Fc Receptor FcγRIIB Induces CD8+ T Cell Apoptosis to Limit T Cell Immunity

Morris, Anna B.; Farley, Clara R.; Pinelli, David F.; Adams, Layne E.; Cragg, Mark S.; Boss, Jeremy M.; Scharer, Christopher D.; Fribourg, Miguel; Cravedi, Paolo; Heeger, Peter S.; Ford, Mandy L.

doi:10.1016/j.immuni.2019.12.006

Cited by 74 publications

(96 citation statements)

References 47 publications

(55 reference statements)

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“…Emerging evidence has demonstrated that FcγRIIB is expressed on a subset of polyfunctional CD44 hi CD8 + T cells 21,22. To understand whether pathogen stimulation history affects the expression of the inhibitory Fcγ receptor FcγRIIB on memory CD8 + T cells, we probed CD44 hi Thy1.1 + donor‐specific CD8 + T cells elicited by the different infections for expression of FcγRIIB on days 8 and 28.…”

Section: Resultsmentioning

confidence: 99%

“…However, emerging evidence suggests that effector CD8 + T cells can express FcγRIIB 21. Work from our group has further shown that not only can effector CD8 + T cells express FcγRIIB but also that this receptor modulates T cell survival in a cell‐intrinsic manner during primary immune responses in models of transplantation and melanoma 22…”

Section: Introductionmentioning

confidence: 95%

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Memory T cell–mediated rejection is mitigated by FcγRIIB expression on CD8+ T cells

Morris

Pinelli

Liu

et al. 2020

American Journal of Transplantation

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T cell-mediated rejection is a major risk that limits long-term allograft survival and can necessitate retransplantation. Due to their rapid ability to exhibit effector function after reencountering antigen, graft-specific memory T cells in particular can pose a dangerous threat to transplanted organs. Seminal studies have shown that the quantity of donor-reactive alloreactive memory T cells present prior to transplantation is associated with risk of T cell-mediated rejection and are a barrier to tolerance induction.1,2 In addition, we have previously shown that the quality of memory T cells, including cell-surface phenotype and differentiation status, is a determinant of the relative risk posed by memory T cell populations.3,4 Donor-specific memory T cells can be elicited via past transfusion, transplant, or pregnancy, and via the process of heterologous immunity, in which pathogen-elicited memory T cells cross-react with alloantigens and cause damage to the graft.5-7 Novel pathways that modulate memory T cell survival or functionality may represent useful potential

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Memory T cell–mediated rejection is mitigated by FcγRIIB expression on CD8+ T cells

Morris

Pinelli

Liu

et al. 2020

American Journal of Transplantation

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“…FGL2 knockdown in mice will be performed in the future. Previous studies have demonstrated that FGL2 could specifically bind to FcγR receptors, including FcγRIIB (41)(42)(43). FcγRIIB is a transmembrane protein that is abundantly expressed on the surface of myeloid cells (44,45).…”

Section: Discussionmentioning

confidence: 99%

Fibrinogen‑like protein 2 promotes the accumulation of myeloid‑derived suppressor cells in the hepatocellular carcinoma tumor microenvironment

et al. 2020

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The tumor microenvironment in hepatocellular carcinoma can be classified into cellular and non-cellular components. Myeloid-derived suppressor cells (MDSCs) are cellular components of this microenvironment that serve an important role in the progression of hepatocellular carcinoma. Fibrinogen-like protein 2 (FGL2) has been demonstrated to promote tumor progression by regulating cellular components of the tumor microenvironment in various types of malignant tumor. The present study aimed to determine the expression of FGL2 in hepatocellular carcinoma and its effect on the tumor microenvironment in order to determine novel targets for liver cancer treatment. Immunohistochemistry and reverse transcription quantitative PCR were performed to determine the expression level of FGL2 and the correlation with surface markers of human MDSCs in hepatocellular carcinoma. Furthermore, a mouse hepatocellular carcinoma cell line overexpressing FGL2 was established by stable transfection of a lentivirus expressing FGL2. In addition, fresh bone marrow cells extracted from mouse femurs were in vitro cultured using conditioned medium derived from the cell line overexpressing FGL2. An orthotopic hepatocellular carcinoma mouse model was also established. The results demonstrated that FGL2 expression level in hepatocellular carcinoma tissues was closely associated with tumor size. FGL2 level was positively correlated with the expression level of the MDSC surface markers CD11b and CD33 in hepatocellular carcinoma. The in vitro results demonstrated that FGL2 could maintain the undifferentiated state of bone marrow cells, therefore promoting MDSC accumulation. Furthermore, in the orthotopic hepatocellular carcinoma mouse model, we observed that overexpression of FGL2 could promote tumor growth and significantly increase the number of MDSCs in the tumors and spleen. Taken together, these findings suggested that FGL2 may promote hepatocellular carcinoma tumor growth by promoting the accumulation of MDSCs in the tumor microenvironment.

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“…However, there is increasing evidence that T‐lymphocyte populations express FcγR. Some γδ T cells express FcγRIIIa and αβ T cells reportedly express FcγRIIa, FcγRIIb or FcγRIIIa but the significance with respect to effector function mediated by antibody is presently unclear 24‐28…”

Section: Human Fcγr General Propertiesmentioning

confidence: 99%

Harnessing the immune system via FcγR function in immune therapy: a pathway to next‐gen mAbs

et al. 2020

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The human fragment crystallizable (Fc)c receptor (R) interacts with antigencomplexed immunoglobulin (Ig)G ligands to both activate and modulate a powerful network of inflammatory host-protective effector functions that are key to the normal physiology of immune resistance to pathogens. More than 100 therapeutic monoclonal antibodies (mAbs) are approved or in late stage clinical trials, many of which harness the potent FccR-mediated effector systems to varying degrees. This is most evident for antibodies targeting cancer cells inducing antibody-dependent killing or phagocytosis but is also true to some degree for the mAbs that neutralize or remove small macromolecules such as cytokines or other Igs. The use of mAb therapeutics has also revealed a "scaffolding" role for FccR which, in different contexts, may either underpin the therapeutic mAb action such as immune agonism or trigger catastrophic adverse effects. The still unmet therapeutic need in many cancers, inflammatory diseases or emerging infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires increased effort on the development of improved and novel mAbs. A more mature appreciation of the immunobiology of individual FccR function and the complexity of the relationships between FccRs and antibodies is fueling efforts to develop more potent "next-gen" therapeutic antibodies. Such development strategies now include focused glycan or protein engineering of the Fc to increase affinity and/or tailor specificity for selective engagement of individual activating FccRs or the inhibitory FccRIIb or alternatively, for the ablation of FccR interaction altogether. This review touches on recent aspects of FccR and IgG immunobiology and its relationship with the present and future actions of therapeutic mAbs.

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Signaling through the Inhibitory Fc Receptor FcγRIIB Induces CD8+ T Cell Apoptosis to Limit T Cell Immunity

Cited by 74 publications

References 47 publications

Memory T cell–mediated rejection is mitigated by FcγRIIB expression on CD8+ T cells

Memory T cell–mediated rejection is mitigated by FcγRIIB expression on CD8+ T cells

Fibrinogen‑like protein 2 promotes the accumulation of myeloid‑derived suppressor cells in the hepatocellular carcinoma tumor microenvironment

Harnessing the immune system via FcγR function in immune therapy: a pathway to next‐gen mAbs

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