On the Role of Regulatory T Cells during Viral-Induced Inflammatory Lesions

Veiga-Parga, Tamara; Suryawanshi, Amol; Mulik, Sachin; Gimenez, Fernanda; Sharma, Shalini; Sparwasser, Tim; Rouse, Barry T.

doi:10.4049/jimmunol.1202322

Cited by 55 publications

(57 citation statements)

References 40 publications

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“…Depletion of NK cells has been shown to enhance mCMV titers and mCMV-specific T cell responses during acute mCMV infection (22)(23)(24)(25)(26), which might be the reason for the strong effect reported by Arens et al (20). Unlike with mCMV, the expansion of Tregs has been found in mice infected with other herpesviruses, like herpes simplex virus (HSV) (12,27). It is currently not known why mCMV induces such weak Treg responses, which is clearly different from what occurs in many other viral infections.…”

Section: Fig 3 Mcmv-specific Cd8mentioning

confidence: 86%

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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Section: Fig 3 Mcmv-specific Cd8mentioning

confidence: 86%

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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“…MDSCs or MDSC-LCs accumulated in HSV-1-infected corneas (34,130,154), but it remains unclear whether these cells demonstrated inhibitory activity. In one study, F4/80 -GR1 + cells accrued in the corneas of HSV-1-infected mice and the authors concluded, based on nuclear morphology, that these infiltrating cells were not MDSCs, however, functional studies were not provided (130).…”

Section: T Cellsmentioning

confidence: 99%

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

2017

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Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that are well described as potent immune regulatory cells during human cancer and murine tumor models. Reports of MDSCs during viral infections remain limited, and their association with immunomodulation of viral diseases is still being defined. Here, we provide an overview of MDSCs or MDSC-like cells identified during viral infections, including murine viral models and human viral diseases. Understanding the similarities and/or differences of virally induced versus tumor-derived MDSCs will be important for designing future immunotherapeutic approaches.

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“…Treg cells play a critical role of regulating effector T cells, NK cells, neutrophils, monocytes, and macrophages early during viral infections, mitigating the pathology incurred by the immune response and prolonging survival of the infected mice (57)(58)(59)(60). The presence of virus-specific memory Treg cells can preserve lung function by limiting CD8 T cell response and reduc- ing pathology during homologous influenza rechallenge (61).…”

Section: Figmentioning

confidence: 99%

Regulatory T Cells Resist Virus Infection-Induced Apoptosis

Wun-Yue

Kraft

Selin

et al. 2015

J Virol

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Regulatory T (Treg) cells are important in the maintenance of self-tolerance, and the depletion of Treg cells correlates with autoimmune development. It has been shown that type I interferon (IFN) responses induced early in the infection of mice can drive memory (CD44hi) CD8 and CD4 T cells into apoptosis, and we questioned here whether the apoptosis of CD44-expressing Treg cells might be involved in the infection-associated autoimmune development. Instead, we found that Treg cells were much more resistant to apoptosis than CD44hi CD8 and CD4 T cells at days 2 to 3 after lymphocytic choriomeningitis virus infection, when type I IFN levels are high. The infection caused a downregulation of the interleukin-7 (IL-7) receptor, needed for survival of conventional T cells, while increasing on Treg cells the expression of the high-affinity IL-2 receptor, needed for STAT5-dependent survival of Treg cells. The stably maintained Treg cells early during infection may explain the relatively low incidence of autoimmune manifestations among infected patients. IMPORTANCEAutoimmune diseases are controlled in part by regulatory T cells (Treg) and are thought to sometimes be initiated by viral infections. We tested the hypothesis that Treg may die off at early stages of infection, when virus-induced factors kill other lymphocyte types. Instead, we found that Treg resisted this cell death, perhaps reducing the tendency of viral infections to cause immune dysfunction and induce autoimmunity.

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On the Role of Regulatory T Cells during Viral-Induced Inflammatory Lesions

Cited by 55 publications

References 40 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

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

Regulatory T Cells Resist Virus Infection-Induced Apoptosis

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