Persistent and Selective Deficiency of CD4+ T Cell Immunity to Cytomegalovirus in Immunocompetent Young Children

Tu, Wenwei; Chen, Sharon; Sharp, Margaret; Dekker, C.N.T.; Manganello, Anne Marie; Tongson, Eileen C.; Maecker, Holden T.; Holmes, Tyson H.; Wang, Zhaoti; Kemble, George; Adler, Stuart P.; Arvin, Ann M.; Lewis, David B.

doi:10.4049/jimmunol.172.5.3260

Cited by 186 publications

(154 citation statements)

References 51 publications

(60 reference statements)

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“…[15][16][17][18] Also, while infection of newborns (which are also considered immunologically immature) does not cause such serious morbidity as infection in utero, viral replication in the young may take a much longer time to be brought under control as evidenced by prolonged shedding of the virus in urine and saliva. 19 Taken together, these data provide reasonable evidence that the immune response mounted during primary infection is effective at limiting lytic viral replication and preventing serious disease. However, despite this, latency is always established and virus is never cleared (Figure 2).…”

Section: Primary Infection and The Immune Response To Virus In Lytic mentioning

confidence: 66%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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While the host immune response following primary human cytomegalovirus (HCMV) infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lytic infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latently infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.

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Section: Primary Infection and The Immune Response To Virus In Lytic mentioning

confidence: 66%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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“…However, introducing a vaccine Ag into the cytoplasm of APCs induces a significant CD8 CTL response even in neonates (3,6,7). Contrary to the induction of CTLs, Th1 (IFN-␥ producing) CD4 T cell responses have not only been difficult to induce in the neonate, but appear even more difficult to sustain (4,5,8,9).…”

Section: Induction Of Protective Immunity Tomentioning

confidence: 99%

Induction of Protective Immunity to Listeria monocytogenes in Neonates

Kollmann

Reikie

Blimkie

et al. 2007

The Journal of Immunology

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Neonates suffer unduly from infections and also respond suboptimally to most commonly used vaccines. However, a CD8 T cell response can be elicited in neonates if the Ag is introduced into the cytoplasm of APCs. Listeria monocytogenes (Lm) targets the cytoplasm of APC and is a strong CD8 and CD4 Th1-promoting vaccine vehicle in adult mice. We hypothesized that an attenuated strain of Lm would be safe and induce long-lasting protective immunity, even in neonates. We found that neonatal mice immunized only once with the attenuated strain ΔactA-Lm developed robust primary and secondary CD8 and CD4 Th1 responses and were fully protected from lethal challenge with virulent wild-type Lm without the need for a booster immunization. Furthermore, ΔactA-Lm expressing a heterologous recombinant Ag induced a strong CD8 and Th1 memory response to that Ag. Based on these data, we propose that ΔactA-Lm or derivatives thereof might serve as a vaccine vehicle for neonatal immunization.

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“…In contrast, despite the accumulating evidence for an importance of CD4 + T cells in CMV immune surveillance, virus-specific CD4 + T-cell responses, with respect to their development and function, remain poorly defined. In humans, the presence of CMV-specific CD4 + T cells correlates with virus control in renal transplant patients [10] and impaired induction of CMV-specific CD4 + T cells correlates with prolonged virus shedding in children with CMV viremia [11]. Furthermore, CD4 + T cells have been shown to play a role in the maintenance of antiviral CD8 + T-cell response in patients undergoing allogeneic BM or solid organ transplantation [12,13].…”

Section: Introductionmentioning

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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Persistent and Selective Deficiency of CD4+ T Cell Immunity to Cytomegalovirus in Immunocompetent Young Children

Cited by 186 publications

References 51 publications

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

Induction of Protective Immunity to Listeria monocytogenes in Neonates

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

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Persistent and Selective Deficiency of CD4+ T Cell Immunity to Cytomegalovirus in Immunocompetent Young Children

Cited by 186 publications

References 51 publications

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

Induction of Protective Immunity to Listeria monocytogenes in Neonates

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

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