Emergence of a CD4+CD28− Granzyme B+, Cytomegalovirus-Specific T Cell Subset after Recovery of Primary Cytomegalovirus Infection

Leeuwen, Ester M. M. van; Remmerswaal, Ester B. M.; Vossen, Mireille T. M.; Rowshani, Ajda T.; Dillen, Pauline M. E. Wertheim-van; Lier, René A. W. van; Berge, Ineke J. M. ten

doi:10.4049/jimmunol.173.3.1834

Cited by 318 publications

(318 citation statements)

References 52 publications

(46 reference statements)

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“…3B) and granzyme B (data not shown), thus corresponding to a described subset of HCMV-specific CD4 + CTL [43]; it is noteworthy that both perforin and granzyme B were also detected in CD4 + NKG2D -cells ( Fig. 3B; data not shown).…”

Section: Distribution Of Ilt2 Kir and Cd94/nkg2 Nkr On Hcmv-stimulatmentioning

confidence: 72%

Expression and function of NKG2D in CD4⁺ T cells specific for human cytomegalovirus

et al. 2006

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The human NKG2D killer lectin‐like receptor (KLR) is coupled by the DAP10 adapter to phosphoinositide 3‐kinase (PI3 K) and specifically interacts with different stress‐inducible molecules (i.e. MICA, MICB, ULBP) displayed by some tumour and virus‐infected cells. This KLR is commonly expressed by human NK cells as well as TCRγδ+ and TCRαβ+CD8+ T lymphocytes, but it has been also detected in CD4+ T cells from rheumatoid arthritis and cancer patients. In the present study, we analysed NKG2D expression in human cytomegalovirus (HCMV)‐specific CD4+ T lymphocytes. In vitro stimulation of peripheral blood mononuclear cells (PBMC) from healthy seropositive individuals with HCMV promoted variable expansion of CD4+NKG2D+ T lymphocytes that coexpressed perforin. NKG2D was detected in CD28– and CD28dull subsets and was not systematically associated with the expression of other NK cell receptors (i.e. KIR, CD94/NKG2 and ILT2). Engagement of NKG2D with specific mAb synergized with TCR‐dependent activation of CD4+ T cells, triggering proliferation and cytokine production (i.e. IFN‐γ and TNF‐α). Altogether, the data support the notion that NKG2D functions as a prototypic costimulatory receptor in a subset of HCMV‐specific CD4+ T lymphocytes and thus may have a role in the response against infected HLA class II+ cells displaying NKG2D ligands.

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Section: Distribution Of Ilt2 Kir and Cd94/nkg2 Nkr On Hcmv-stimulatmentioning

confidence: 72%

Expression and function of NKG2D in CD4⁺ T cells specific for human cytomegalovirus

et al. 2006

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“…The appearance of HCMV-specific IFN-γ-producing CD4 + T cells in asymptomatic recipients of CMV-positive allotransplants was specifically correlated with containment of viral control [38] and CD4 + T-cell lines specific for certain HCMV CD4 + T-cell antigens were shown to be cytolytic [23,35]. Interestingly, a very recent study reported the existence of high numbers of multifunctional pp65-specific CD4 + T cells in bronchoalveolar lavage-derived lung mononuclear cells of lung transplant recipients with chronic CMV infection, which correlated with mucosal viral control [39].…”

Section: Discussionmentioning

confidence: 99%

“…In a mouse model of pathogenic MCMV infection of hemoablated recipients, CD4 + T cells were considered not to display direct antiviral activity [33] and thus were generally not considered for T-cell immunotherapy protocols. However, studies of HCMV-specific CD4 + T cells in humans [34,35] and recent clinical studies [36] have indicated a possible protective role of CMV-specific CD4 + T-cell-mediated immunity. In this study, using a recently developed TCR transgenic mouse recognizing an MCMV-specific CD4 + T-cell epitope within the M25 protein, we characterized the development, phenotype, and antiviral functions of virus-specific CD4 + T cells during Our data provide direct evidence for a role of MCMV-specific CD4 + T cells in adoptive T-cell immunotherapy of CMV disease.…”

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confidence: 99%

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

et al. 2013

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Cytomegalovirus (CMV) infects a majority of the human population and establishes a lifelong persistence. CMV infection is usually asymptomatic but the virus carries pathogenic potential and causes severe disease in immunocompromised individuals. T-cell-mediated immunity plays an essential role in control of CMV infection and adoptive transfer of CMVspecific CD8 + T cells restores viral immunity in immunosuppressed patients but a role for CD4 + T cells remains elusive. Here, we analyzed in adoptive transfer studies the features and antiviral functions of virus-specific CD4 + T cells during primary murine CMV (MCMV) infection. MCMV-specific CD4 + T cells expanded upon MCMV infection and displayed an effector phenotype and function. Adoptive transfer of in vivo activated MCMV-specific CD4 + T cells to immune-compromised mice was protective during pathogenic MCMVinfection and IFN-γ was a crucial mediator of this protective capacity. Moreover, cotransfer of low doses of both MCMV-specific CD4 + T cells and CD8 + T cells synergized in control of lytic viral replication in immune-compromised mice. Our data reveal a pivotal antiviral role for virus-specific CD4 + T cells in protection from pathogenic CMV infection and provide evidence for their antiviral therapeutic potential. Keywords: Adoptive immunotherapy r CD4 + T cells r Cytomegalovirus infectionAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionImmunity to viral infections relies on effector mechanisms exerted by different components of the immune system. Despite the prominent roles of cytotoxic CD8 + T cells and neutralizing antibodies in controlling viral infections, there is growing evidence for an antiviral role of CD4 + helper T cells, not only in provision of help to other effector cells, but also in exertion of direct antiviral functions either by secretion of cytokines or exertion of cytotoxicity [1]. CD4 + T-cell-mediated protective immunity has been reported Correspondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch for a number of viral infections [2][3][4][5]; however, the antiviral effector mechanisms exerted by CD4 + T cells in vivo have remained poorly characterized.Cytomegalovirus (CMV) is a β-herpes virus that infects a majority of the human population worldwide. After resolution of primary infection, this large DNA β-herpes virus establishes a life-long persistence in its host. CMV infection is usually clinically silent in healthy individuals. Nevertheless, CMV-infected immunosuppressed patients, such as hematopoietic BM or solid organ transplant recipients, suffer from CMV disease with potentially * These authors have contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2886-2895 Immunity to Infection 2887 severe clinical outcome [6]. Cellular immunity is important to control CMV infection [7,8] Results Expansion, activation, and phenotype of M25-specific CD4 + T cells during acute ...

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“…These cells were found to be MHC class IIrestricted cytotoxic T-cells. 41,42 Cassaza 22 reported their ability to kill CMV Ag-loaded B-LCLs.…”

Section: Discussionmentioning

confidence: 99%

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

Krol

Stuchlý

Hubáček

et al. 2010

Bone Marrow Transplant

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Depletion of cellular immunity as a consequence of conditioning before allogeneic hematopoietic SCT (HSCT) frequently results in CMV reactivation, which may in turn lead to life-threatening infections and require timely antiviral treatment. We have investigated the functional signatures of CMV-specific CD4 þ and CD8 þ T-cells in 191 samples from 118 individuals. We compared healthy donors with both patients with high and undetectable viral loads, and those who controlled and did not control their CMV reactivations. Polychromatic flowcytometric measurements of CD154 (CD40L), intracellular cytokines (IFNc, IL2) and a degranulation marker (CD107a) allowed us to assess the functional status of various T-cells simultaneously. We found that dual IFNc/ IL2-producing CD8 þ T-cells were present in patients controlling their CMV reactivations but absent from noncontrollers. CD8 þ T-cells that produce only IFNc were the most abundant subtype, but they most likely represent non-protective memory cells. Distinct functional signatures were examined by hierarchical clustering, and this revealed that, unlike polyfunctional CD8 þ T-cells, CD8 þ T-cells that produce IFNc alone were not functioning in concert with other subsets. In conclusion, our study revealed functional signatures that may be useful for immune monitoring, and it could change the interpretation of previous studies that assessed only IFNc.

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Emergence of a CD4+CD28− Granzyme B+, Cytomegalovirus-Specific T Cell Subset after Recovery of Primary Cytomegalovirus Infection

Cited by 318 publications

References 52 publications

Expression and function of NKG2D in CD4⁺ T cells specific for human cytomegalovirus

Expression and function of NKG2D in CD4⁺ T cells specific for human cytomegalovirus

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

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

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Emergence of a CD4+CD28− Granzyme B+, Cytomegalovirus-Specific T Cell Subset after Recovery of Primary Cytomegalovirus Infection

Cited by 318 publications

References 52 publications

Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus

Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus

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

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

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Expression and function of NKG2D in CD4⁺ T cells specific for human cytomegalovirus

Expression and function of NKG2D in CD4⁺ T cells specific for human cytomegalovirus

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