Effector Memory αβ T Lymphocytes Can Express FcγRIIIa and Mediate Antibody-Dependent Cellular Cytotoxicity

Clémenceau, Béatrice; Vivien, Régine; Berthomé, Mathilde; Robillard, Nelly; Garand, Richard; Gallot, Géraldine; Vollant, Solène; Vié, Henri

doi:10.4049/jimmunol.180.8.5327

Cited by 54 publications

(58 citation statements)

References 43 publications

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“…However, it is now clear that subpopulations of conventional T cells both in the mouse (10, 29 -35) and in humans (36 -39) do endogenously express Fc␥R or subunits of the Fc␥R complex. Apart from ␥␦T cells and NK T cells, this is for instance the case of double-negative T cells (32), some conventional CD4 ϩ or CD8 ϩ ␣␤T cells exhibiting an activated phenotype (18,36,39), and some tumor-infiltrating lymphocytes (40). Expression of Fc␥R by these cells was shown to confer onto them novel biological functions, such as the ability to perform ADCC (18, 35, 36, 39), to produce lymphokines (35, 41, 42) and, in the case of the FcR␥ subunit, to functionally replace the -chain in the TCR complex (37,43,44).…”

Section: Discussionmentioning

confidence: 99%

Ligand Binding but Undetected Functional Response of FcR after Their Capture by T Cells via Trogocytosis

Hudrisier

Clémenceau

Balor

et al. 2009

The Journal of Immunology

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Intercellular transfer of cell surface proteins by trogocytosis is common and could affect T cell responses. Yet, the role of trogocytosis in T cell function is still elusive, and it is unknown whether a molecule, once captured by T cells, harbors the same biological properties as in donor APC. In this study, we showed that FcγR as well as the associated FcRγ subunit could be detected at high levels on murine and human T cells after their intercellular transfer from FcγR-expressing APC. Capture of FcγR occurred during coculture of T cells with FcγR-expressing APC upon Ab- or Ag-mediated T cell stimulation. Once captured by T cells, FcγR were expressed in a conformation compatible with physiological function and conferred upon T cells the ability to bind immune complexes and to provision B cells with this source of Ag. However, we were unable to detect downstream signal or signaling-dependent function following the stimulation of FcγR captured by T cells, and biochemical studies suggested the improper integration of FcγR in the recipient T cell membrane. Thus, our study demonstrates that T cells capture FcγR that can efficiently exert ligand-binding activity, which, per se, could have functional consequences in T cell-B cell cooperation.

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Section: Discussionmentioning

confidence: 99%

Ligand Binding but Undetected Functional Response of FcR after Their Capture by T Cells via Trogocytosis

Hudrisier

Clémenceau

Balor

et al. 2009

The Journal of Immunology

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“…Natural killer (NK) cells are usually considered as the main effector of ADCC, but evidence for a role of this process in immune defense against HCMV is sparse. Discrete subsets of CD8 ␣␤ T lymphocytes have also been described to express CD16 and to perform ADCC in few diseases, such as chronic hepatitis C virus infection 5 and hyperlymphocytosis, 6 but this has never been reported in HCMV infection.…”

Section: Introductionmentioning

confidence: 99%

Antibody-dependent anti-cytomegalovirus activity of human γδ T cells expressing CD16 (FcγRIIIa)

Couzi

Pitard

Sicard

et al. 2012

Blood

120

116

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Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in transplant recipients. Long-term protective immunity against HCMV requires both sustained specific T-cell response and neutralizing IgG production, but the interplay between these effector arms remains poorly defined. We previously demonstrated that ␥␦ T cells play a substantial role as anti-HCMV Tcell effectors. The observation that CD16 (Fc␥RIIIA) was specifically expressed by the majority of HCMV-induced ␥␦ T cells prompted us to investigate their cooperation with anti-HCMV IgG. We found that CD16 could stimulate ␥␦ T cells independently of T-cell receptor (TCR) engagement and provide them with an intrinsic antibody-dependent cell-mediated cytotoxic ( IntroductionHuman cytomegalovirus (HCMV) is a widespread herpesvirus with an average seroprevalence of around 50% that increases with age and low socioeconomic status. Primary HCMV infection in an immunocompetent host is asymptomatic, but the virus establishes lifelong latency probably associated with periodic reactivation episodes. Conversely, damaging clinical symptoms can be observed in the course of HCMV infection in fetuses, neonates, and immunocompromised patients, such as those infected with HIV, recipients of solid organ allografts, or undergoing allogeneic hematopoietic stem cell transplantation. Constant immune surveillance is thus critical to keep the virus in check, and actually HCMV is highly immunogenic and elicits all the arsenal of the host immune defense. 1 The early events associated with virus entry into host cells first trigger a robust production of type I IFN and inflammatory cytokines, such as IL12, which are critical for the recruitment and activation of innate immune cells, particularly phagocytic leukocytes. 2 The activated innate immune cells then initiate the development of a vigorous adaptive immune response that culminates with the production of neutralizing antiviral antibodies (Abs) and IFN␥-producing and/or cytotoxic CD8 T cells. Both of these effectors are required for the establishment of long-lasting immunity against HCMV reactivation, superinfection, and congenital infection, but the cooperation between humoral immunity and T-cell effectors remains to be clarified.Humoral response against HCMV is characterized by the production of neutralizing Abs directed against viral envelope glycoproteins (mostly gB and gH) and gene products of the UL131A-128 locus, which are involved in virus attachment and entry into host cells. 3 However, the majority (90%) of HCMVspecific Abs do not have virus-neutralizing activity. 4 Such Abs could cooperate with cell effectors expressing CD16, the low affinity Fc receptor for IgG (FcR␥IIIa), to generate an Abdependent cell-mediated cytotoxicity (ADCC). However, ADCC would require that Abs are directed against HCMV-infected cells, something that has never been reported. Natural killer (NK) cells are usually considered as the main effector of ADCC, but evidence for a role of this process in immune defense again...

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“…þ a/b-T cells and CD16 þ g/d-T cells are involved in ADCC-mediated antiviral activity in vivo, independently of human leukocyte antigen (HLA) restriction (11)(12)(13). The binding affinity of the FcgRIIIa-158(Valine/ Valine) homodimer (158V/V) to immunoglobulin G (IgG)1 and IgG3 is much higher than that of the FcgRIIIa-158 (Phenylalanine/Phenylalanine) homodimer (158F/F; ref.…”

Section: Introductionmentioning

confidence: 99%

Gene-Modified Human α/β-T Cells Expressing a Chimeric CD16-CD3ζ Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy

Ochi

Fujiwara

Tanimoto

et al. 2014

Cancer Immunology Research

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The central tumoricidal activity of anticancer monoclonal antibodies (mAb) is exerted by FcgR IIIa (CD16)-expressing effector cells in vivo via antibody-dependent cell-mediated cytotoxicity (ADCC), as observed for natural killer (NK) cells. In practice, chemotherapy-induced leukopenia and exhaustion of NK cells resulting from ADCC often hamper the clinical efficacy of cancer treatment. To circumvent this drawback, we examined in vivo the feasibility of T cells, gene-modified to express a newly generated affinity-matured (158V/V) chimeric CD16-CD3z receptor (cCD16z-T cells), as a transferable alternative effector for cancer mAb therapy. cCD16z-T cells were readily expandable in ex vivo culture using anti-CD2/CD3/CD28 beads and recombinant human interleukin-2 (rhIL-2), and they successfully displayed ADCC-mediated tumoricidal activity in vitro. During ADCC, ligation of opsonized cancer cells to the introduced cCD16z-T cells stimulated the effector cells to produce proinflammatory cytokines and release toxic granules through the activation of the Nuclear factor of activated T cells (NFAT) pathway after phosphorylation of the CD3z chain. In parallel, these stimulated cCD16z-T cells transiently proliferated and differentiated into effector memory T cells. In contrast, NK cells activated by rhIL-2 displayed similar ADCC activity, but failed to proliferate. Human cCD16z-T cells infused concomitantly with anti-CD20 mAb synergistically inhibited the growth of disseminated Raji cells, a CD20þ lymphoma cell line, in immunodeficient mice, whereas similarly infused rhIL-2-treated NK cells survived for a shorter time and displayed less effective tumor suppression. Our findings strongly suggest the clinical feasibility of cCD16z-T cells as adoptively transferable ADCC effector cells that could potentially enhance the clinical responses mediated by currently available anticancer mAbs.

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Effector Memory αβ T Lymphocytes Can Express FcγRIIIa and Mediate Antibody-Dependent Cellular Cytotoxicity

Cited by 54 publications

References 43 publications

Ligand Binding but Undetected Functional Response of FcR after Their Capture by T Cells via Trogocytosis

Ligand Binding but Undetected Functional Response of FcR after Their Capture by T Cells via Trogocytosis

Antibody-dependent anti-cytomegalovirus activity of human γδ T cells expressing CD16 (FcγRIIIa)

Gene-Modified Human α/β-T Cells Expressing a Chimeric CD16-CD3ζ Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy

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