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

Abstract

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...

Immunoactivation induced by chronic viral infection inhibits viral replication and drives immunosuppression through sustained IFN‐I responses

“…Additionally, several studies using the lymphocytic choriomeningitis virus (LCMV) model have shown that NK cells, the development or reduction in the number of dendritic cells (DCs), and CD8 + T-cell-mediated immunopathology contribute to immunosuppression [2,[13][14][15]. This finding is in line with observations from studies of infections with other viruses showing that constant activation of CD8 + T cells in lymph nodes and spleen alters immune function [2,11]. It has been reported that LCMV infects B cells that produce neutralizing antibodies, which will be eliminated by immunopathological LCMV-specific CD8 + T cells [2].…”

Activated regulatory T cells suppress effector NK cell responses by an IL-2-mediated mechanism during an acute retroviral infection

“…Lindenberg and colleagues [ 23 ] showed that during acute mouse CMV infection Tregs suppress only T cell responses, whereas NK cell responses were not affected by Tregs. However, CMV infection of mice is not a very useful model to study the interaction of Tregs and NK cells because the virus does not efficiently activate or expand Tregs [ 40 ]. The effect of virus-induced Tregs on anti-viral NK cell responses can only be investigated in an infection model with strong Treg responses, like the FV mouse model [ 9 , 41 ].…”

Reactive glia promote development of CD103+CD69+ CD8+ T‐cells through programmed cell death‐ligand 1 (PD‐L1)

“…In our previous study, we used a well‐established mouse model of MCMV brain infection to demonstrate a role for the PD‐1: PD‐L1 pathway in development of CD103 + CD69 + CD8 + bT RM populations in vivo following acute viral infection . Here, we followed‐up on those findings by first demonstrating that some of the bT RM were specific for a previously identified viral T‐cell epitope . We infected wild‐type (WT) C57BL/6 and PD‐L1 KO mice intracerebroventricularly with MCMV and evaluated expression of CD103 (marker for T RM ) on antigen‐specific CD8 + T‐cells at 30 days post‐infection (dpi).…”

“…In our previous study, we used a well-established mouse model of MCMV brain infection to demonstrate a role for the PD-1: PD-L1 pathway in development of CD103 þ CD69 þ CD8 þ bT RM populations in vivo following acute viral infection [10]. Here, we followed-up on those findings by first demonstrating that some of the bT RM were specific for a previously identified viral T-cell epitope [38].…”