Adoptive transfer of cytomegalovirus‐specific effector <scp>CD</scp>4<sup>+</sup><scp>T</scp> cells provides antiviral protection from murine <scp>CMV</scp> infection

Jeitziner, Sanja Mandaric; Walton, Senta M.; Torti, Nicole; Oxenius, Annette

doi:10.1002/eji.201343690

Cited by 41 publications

(38 citation statements)

References 43 publications

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“…In mice, CD4 T cells are absolutely required to control mouse cytomegalovirus (MCMV) replication in the salivary glands-the key site of viral dissemination, where CD8 T cells can exert no control (14,15)-and also contribute to immune control in several other organs. Adoptive transfer of MCMV-specific transgenic CD4 T cells provides some protection in immunocompromised mice (16), and cotransferring CMV-specific CD4 T cells reduces viral load and promotes "help" for CMV-specific CD8 T cell responses in patients receiving cellular immunotherapy (17).…”

mentioning

confidence: 99%

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

Verma

Weiskopf

Gupta

et al. 2016

J Virol

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CD4 T cells provide protection against cytomegalovirus (CMV) and other persistent viruses, and the ability to quantify and characterize epitope-specific responses is essential to gain a more precise understanding of their effector roles in this regard. Here, we report the first two I-A d -restricted CD4 T cell responses specific for mouse CMV (MCMV) epitopes and use a major histocompatibility complex class II (MHC-II) tetramer to characterize their phenotypes and functions. We demonstrate that MCMV-specific CD4 T cells can express high levels of granzyme B and kill target cells in an epitope-and organ-specific manner. In addition, CD4 T cell epitope vaccination of immunocompetent mice reduced MCMV replication in the same organs where CD4 cytotoxic T lymphocyte (CTL) activity was observed. Together, our studies show that MCMV epitope-specific CD4 T cells have the potential to mediate antiviral defense by multiple effector mechanisms in vivo. C ytomegalovirus (CMV)/human herpesvirus 5 (HHV-5) (the prototypic betaherpesvirus) infection is endemic in humans and wild mice and establishes a lifelong infection in the absence of acute disease in healthy hosts. Adaptive immunity is a critical component of CMV defenses, restricting primary infection and dampening reactivation, helping to maintain the largely benign host-virus equilibrium. However, if immunity is naive or compromised (e.g., in transplant recipients or congenital infection), CMV can cause serious disease (1, 2). In immunocompetent mice, CD8 T cells help to control acute CMV infection and establish latency (3, 4), and their adoptive transfer prevents disease in mice and humans with weakened immunity (5-8). Although much less well studied, CD4 T cells also contribute to defense against CMV. Their rapid expansion and numbers correlate with reduced disease in transplant and HIV patients (9-11), and correspondingly, delayed induction of CMV-specific CD4 T cells is associated with increased congenital infection (12) and prolonged viral shedding in infants (13). Notably, no protective correlates were seen with CMV-specific CD8 T cell responses in several of these studies. In mice, CD4 T cells are absolutely required to control mouse cytomegalovirus (MCMV) replication in the salivary glands-the key site of viral dissemination, where CD8 T cells can exert no control (14, 15)-and also contribute to immune control in several other organs. Adoptive transfer of MCMV-specific transgenic CD4 T cells provides some protection in immunocompromised mice (16), and cotransferring CMV-specific CD4 T cells reduces viral load and promotes "help" for CMV-specific CD8 T cell responses in patients receiving cellular immunotherapy (17).In addition to traditional helper functions, CD4 T cells can also mediate direct antiviral activity in some cases. In chronic human CMV (HCMV), Epstein-Barr virus (EBV), and HIV infections, CD4 T cells displaying a terminally differentiated effector phenotype and/or expressing canonical cytolytic molecules (e.g., granzymes and perforin) are pres...

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confidence: 99%

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

Verma

Weiskopf

Gupta

et al. 2016

J Virol

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“…Walton et al revealed that the mechanism of CD4 T cell immune control in the salivary glands of MCMV infected mice was via direct secretion of IFN-γ, which induced antiviral signaling on non-hematopoietic cells (134). Adoptive transfer experiments of MCMV-specific effector CD4 T cells to immune-compromised mice was found to be protective during pathogenic MCMV infection and IFN-γ was a vital mediator of this protective capacity (135). Despite the apparent importance of CD4 T cells in viral control in the above studies, there was no specific link to CD4 CTL.…”

Section: Infections In Which Cd4 Ctl Are Protectivementioning

confidence: 99%

Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

et al. 2017

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CD4 T cells with cytotoxic function were once thought to be an artifact due to long-term in vitro cultures but have in more recent years become accepted and reported in the literature in response to a number of viral infections. In this review, we focus on cytotoxic CD4 T cells in the context of human viral infections and in some infections that affect mice and non-human primates. We examine the effector mechanisms used by cytotoxic CD4 cells, the phenotypes that describe this population, and the transcription factors and pathways that lead to their induction following infection. We further consider the cells that are the predominant targets of this effector subset and describe the viral infections in which CD4 cytotoxic T lymphocytes have been shown to play a protective or pathologic role. Cytotoxic CD4 T cells are detected in the circulation at much higher levels than previously realized and are now recognized to have an important role in the immune response to viral infections.

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“…While the humoral and innate responses are essential for the early response to infection [1, 3, 4], cellular immunity is required to control latency and prevent CMV reactivation in latently infected individuals [1]. CD8 + cytotoxic T cells (CTL) and CD4 + T helper (Th) cells are both required to assure efficient immune protection against CMV reactivation [1, 5–8]. Primary infection is dominated by CD8 + T cell response, preferentially targeting CMV immediate early-1 (IE-1) antigen, while long-term recovery is dominated by CD4 + T cell response and a switch of reactivity toward CMV lower matrix phosphoprotein 65 (pp65) [6, 8–11].…”

Section: Introductionmentioning

confidence: 99%

Validation of T-Track® CMV to assess the functionality of cytomegalovirus-reactive cell-mediated immunity in hemodialysis patients

et al. 2017

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BackgroundUncontrolled cytomegalovirus (CMV) replication in immunocompromised solid-organ transplant recipients is a clinically relevant issue and an indication of impaired CMV-specific cell-mediated immunity (CMI). Primary aim of this study was to assess the suitability of the immune monitoring tool T-Track® CMV to determine CMV-reactive CMI in a cohort of hemodialysis patients representative of patients eligible for renal transplantation. Positive and negative agreement of T-Track® CMV with CMV serology was examined in 124 hemodialysis patients, of whom 67 (54%) revealed a positive CMV serostatus. Secondary aim of the study was to evaluate T-Track® CMV performance against two unrelated CMV-specific CMI monitoring assays, QuantiFERON®-CMV and a cocktail of six class I iTAg™ MHC Tetramers.ResultsPositive T-Track® CMV results were obtained in 90% (60/67) of CMV-seropositive hemodialysis patients. In comparison, 73% (45/62) and 77% (40/52) positive agreement with CMV serology was achieved using QuantiFERON®-CMV and iTAg™ MHC Tetramer. Positive T-Track® CMV responses in CMV-seropositive patients were dominated by pp65-reactive cells (58/67 [87%]), while IE-1-responsive cells contributed to an improved (87% to 90%) positive agreement of T-Track® CMV with CMV serology. Interestingly, T-Track® CMV, QuantiFERON®-CMV and iTAg™ MHC Tetramers showed 79% (45/57), 87% (48/55) and 93% (42/45) negative agreement with serology, respectively, and a strong inter-assay variability. Notably, T-Track® CMV was able to detect IE-1-reactive cells in blood samples of patients with a negative CMV serology, suggesting either a previous exposure to CMV that yielded a cellular but no humoral immune response, or TCR cross-reactivity with foreign antigens, both suggesting a possible protective immunity against CMV in these patients.ConclusionT-Track® CMV is a highly sensitive assay, enabling the functional assessment of CMV-responsive cells in hemodialysis patients prior to renal transplantation. T-Track® CMV thus represents a valuable immune monitoring tool to identify candidate transplant recipients potentially at increased risk for CMV-related clinical complications.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-017-0194-z) contains supplementary material, which is available to authorized users.

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Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

Cited by 41 publications

References 43 publications

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

Validation of T-Track® CMV to assess the functionality of cytomegalovirus-reactive cell-mediated immunity in hemodialysis patients

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Adoptive transfer of cytomegalovirus‐specific effector CD4+T cells provides antiviral protection from murine CMV infection

Cited by 41 publications

References 43 publications

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

Validation of T-Track® CMV to assess the functionality of cytomegalovirus-reactive cell-mediated immunity in hemodialysis patients

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Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection