Activated CD8+ T Cells Induce Expansion of Vβ5+ Regulatory T Cells via TNFR2 Signaling

Joedicke, Jara J.; Myers, Lara; Carmody, Aaron B.; Messer, Ronald J.; Wajant, Harald; Lang, Karl S.; Lang, Philipp A.; Mak, Tak W.; Hasenkrug, Kim J.; Dittmer, Ulf

doi:10.4049/jimmunol.1400649

Cited by 34 publications

(47 citation statements)

References 76 publications

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“…These effector T cells play a major role in initiating the activation and expansion of different subsets of Tregs (8,10,17).…”

Section: Cd8mentioning

confidence: 99%

“…2). Therefore, lymphocytes were simulated with the mCMV-specific major histocompatibility complex (MHC) class I peptides M45 985-993 (HGIRNASFI), M57 816 -824 (SCLEFWQRV), M102 446 -455 (SIVDLRFAVL), m139 419 -426 (TVYGFCLL), or m141 [15][16][17][18][19][20][21][22][23] (VIDAFSRL), and functional mCMV-specific CD8 ϩ T cells were determined by gamma interferon (IFN-␥) production (7,15). Significant 2-to 3-fold reductions in mCMV-specific IFN-␥ ϩ CD44 ϩ CD8 ϩ T cell numbers were detectable in the spleens of FV/mCMV-superinfected mice compared to numbers in mice infected only with mCMV (Fig.…”

Section: It Is Still Unclear Whether Expanded and Activated Regulatormentioning

confidence: 99%

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Expanded Regulatory T Cells in Chronically Friend Retrovirus-Infected Mice Suppress Immunity to a Murine Cytomegalovirus Superinfection

Duppach

Francois

Joedicke

et al. 2014

J Virol

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It is still unclear whether expanded and activated regulatory T cells (Tregs) in chronic viral infections can influence primary immune responses against superinfections with unrelated viruses. Expanded Tregs found in the spleens of chronically Friend virus (FV)-infected mice decreased murine cytomegalovirus (mCMV)-specific CD8؉ T cell responses during acute mCMV superinfection. This suppression of mCMV-specific T cell immunity was found only in organs with FV-induced Treg expansion. Surprisingly, acute mCMV infection itself did not expand or activate Tregs. P revious infections can influence the immune response to infections with unrelated pathogens, which is called heterologous immunity (1, 2). This phenomenon has been found in closely related and completely unrelated viral infections in humans and in mouse models (3). To date, limited information is available as to whether virus-expanded regulatory T cells (Tregs) in a chronically infected host play a role in heterologous immunity. In this study, we investigated the influence of Friend virus (FV)-expanded Tregs on the primary murine cytomegalovirus (mCMV)-specific CD8 ϩ T cell response during an acute mCMV superinfection.We first confirmed the expansion of Tregs during FV infection by determining the number of Tregs in chronically FV-infected mice in different organs ( Fig. 1a) (4, 5). C57BL/6 mice (males, 8 to 9 weeks old) were infected intravenously with 40,000 spleen focusforming units (SFFU) of FV, and CD4 ϩ Foxp3 ϩ Tregs were measured at day 42 postinfection (6, 7). Significantly enhanced percentages (not shown) and absolute numbers of Tregs were found in the spleens but not in the livers and peritoneal exudate cells (PECs) of chronically FV-infected mice compared to results for naive, age-matched controls (Fig. 1a). FV-expanded Tregs had an activated and differentiated phenotype (CD43 ϩ CD69 ϩ and KLRG-1 ϩ ), in contrast to Tregs from uninfected mice at day 10 and day 42 after FV infection ( Fig. 1c and reference 8, respectively).To investigate whether mCMV infection also induces an expansion of Tregs, naive mice were infected intraperitoneally with 5 ϫ 10 4 PFU of mCMV (Smith strain [7]) and CD4 ϩ Foxp3 ϩ Tregs were analyzed at day 10 postinfection in the spleen, liver, and salivary gland, sites where mCMV replicates (9). Surprisingly, no expansion or activation of Tregs was found in the spleens of acutely mCMV-infected mice, in contrast to what is described for FV or lymphocytic choriomeningitis virus (LCMV) infection (Fig. 1b and c) (10-12). Additionally, no expansion of the V␤5 ϩ CD4 ϩ Foxp3 ϩ Tregs, which recognize self-superantigens expressed by endogenous mouse mammary tumor virus, were detectable in mCMV-infected mice (8, 10, 11; data not shown). Furthermore, Tregs from mCMV-infected mice displayed the same phenotype as Tregs from naive animals (Fig. 1c). This was also the case for later time points after mCMV infection (Ͼ10 days postinfection) (data not shown), indicating that mCMV does not induce Treg responses in C57BL/6 mice.Tregs in influen...

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“…These effector T cells play a major role in initiating the activation and expansion of different subsets of Tregs (8,10,17).…”

Section: Cd8mentioning

confidence: 99%

Section: It Is Still Unclear Whether Expanded and Activated Regulatormentioning

confidence: 99%

Expanded Regulatory T Cells in Chronically Friend Retrovirus-Infected Mice Suppress Immunity to a Murine Cytomegalovirus Superinfection

Duppach

Francois

Joedicke

et al. 2014

J Virol

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“…First, natural thymus-derived Tregs, which constitutively express the high affinity IL-2 receptor, are polyclonally activated by IL-2 secreted by F-MuLV-reactive CD4+ T cells and by GITR ligand expressed on activated B cells (Myers et al 2013;Moore et al 2017). Second, thymus-derived Tregs bearing Vβ5 family TCRβ chains specifically react with a retroviral superantigen encoded Downloaded from https://academic.oup.com/femsre/article-abstract/43/5/435/5489187 by guest on 09 June 2020 by endogenous mouse mammary tumor virus 9 (MMTV9) (Myers et al 2013;Joedicke et al 2014a). This mode of Treg expansion accounts for about one in every 10 Tregs and is modulated by membrane-bound TNF-α signals delivered by F-MuLVreactive CD8+ T cells (Myers et al 2013;Joedicke et al 2014a).…”

Section: Cd4+ T Cell Responsesmentioning

confidence: 99%

“…Second, thymus-derived Tregs bearing Vβ5 family TCRβ chains specifically react with a retroviral superantigen encoded Downloaded from https://academic.oup.com/femsre/article-abstract/43/5/435/5489187 by guest on 09 June 2020 by endogenous mouse mammary tumor virus 9 (MMTV9) (Myers et al 2013;Joedicke et al 2014a). This mode of Treg expansion accounts for about one in every 10 Tregs and is modulated by membrane-bound TNF-α signals delivered by F-MuLVreactive CD8+ T cells (Myers et al 2013;Joedicke et al 2014a). Further details on the Treg response in FV infection were recently reviewed (Hasenkrug, Chougnet and Dittmer 2018).…”

Section: Cd4+ T Cell Responsesmentioning

confidence: 99%

Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

Dittmer

Sutter

Kassiotis

et al. 2019

FEMS Microbiology Reviews

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Approximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we know about viral immunity comes from studies using mouse models. Experiments using the Friend virus (FV) model have been particularly informative in defining highly complex anti-retroviral mechanisms of the intrinsic, innate and adaptive arms of immunity. FV studies have unraveled fundamental principles about how the immune system controls both acute and chronic viral infections. They led to a more complete understanding of retroviral immunity that begins with cellular sensing, production of type I interferons, and the induction of intrinsic restriction factors. Novel mechanisms have been revealed, which demonstrate that these earliest responses affect not only virus replication, but also subsequent innate and adaptive immunity. This review on FV immunity not only surveys the complex host responses to a retroviral infection from acute infection to chronicity, but also highlights the many feedback mechanisms that regulate and counter-regulate the various arms of the immune system. In addition, the discovery of molecular mechanisms of immunity in this model have led to therapeutic interventions with implications for HIV cure and vaccine development.

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“…Interleukin-2 (IL-2) is critical for the maintenance and expansion of Treg cells during homeostatic conditions, [39][40][41][42] but other cytokines, such as tumour necrosis factor and IL-21, also appear to contribute to Treg cell expansion, especially during chronic viral infection. [43][44][45] Many mechanisms have been proposed to explain how Treg cells suppress immune responses, including the role of the CTLA-4, transforming growth factor-b, IL-35 and IL-10 pathways, as well as the IL-2 sink mechanism discussed extensively in the literature. [46][47][48][49][50][51][52] In addition to Treg cells, inhibitory pathways have also been shown to play a critical role in modulating CD8 Tcell exhaustion during chronic infection and cancers.…”

Section: Treg Cells and Pd-1 Suppress Immune Responses During Antigenmentioning

confidence: 99%

CD8 T‐cell regulation by T regulatory cells and the programmed cell death protein 1 pathway

Penaloza-MacMaster

2017

Immunology

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SummaryThe primary function of the immune system is to protect the host from infectious microorganisms and cancers. However, a major component of the immune response involves the direct elimination of cells in the body and the induction of systemic inflammation, which may result in lifethreatening immunopathology. Therefore, the immune system has developed complex mechanisms to regulate itself with a specialized subset of CD4 T lymphocytes (referred to as regulatory T cells) and immune checkpoint pathways, such as the programmed cell death protein 1 pathway. These immune regulatory mechanisms can be exploited by pathogens and tumours to establish persistence in the host, warranting a deeper understanding of how to fine-tune immune responses during these chronic diseases. Here, I discuss various features of immune regulatory pathways and what important aspects must be considered in the next generation of therapies to reverse immune exhaustion, understanding that this process is a natural mechanism to prevent the host from destroying itself.

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Activated CD8+ T Cells Induce Expansion of Vβ5+ Regulatory T Cells via TNFR2 Signaling

Cited by 34 publications

References 76 publications

Expanded Regulatory T Cells in Chronically Friend Retrovirus-Infected Mice Suppress Immunity to a Murine Cytomegalovirus Superinfection

Expanded Regulatory T Cells in Chronically Friend Retrovirus-Infected Mice Suppress Immunity to a Murine Cytomegalovirus Superinfection

Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

CD8 T‐cell regulation by T regulatory cells and the programmed cell death protein 1 pathway

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