Early Increases in Superantigen-Specific Foxp3⁺Regulatory T Cells during Mouse Mammary Tumor Virus Infection

Abstract

Mouse mammary tumor virus (MMTV) is a milk-borne betaretrovirus that has developed strategies to exploit and subvert the host immune system. Here, we show in a natural model of MMTV infection that the virus causes early and progressive increases in superantigen (SAg)-specific Foxp3؉ regulatory T cells (T reg ) in Peyer's patches (PP). These increases were shown to be dependent on the presence of dendritic cells. CD4 Mouse mammary tumor virus (MMTV) is a betaretrovirus transmitted through milk that causes mammary tumors in mice (7,32). The MMTV infection model has provided a valuable tool to study how a pathogen can take advantage of the host immune system, and several strategies of virus-host exploitation have been described for this virus (reviewed in references 1 and 13). In neonatal Peyer's patches (PP), MMTV is thought to infect antigen presenting cells (APCs), which then present a virus-encoded superantigen (SAg) to T cells expressing SAgspecific T-cell receptor V␤ chains (9). The resulting interaction is critical since it leads to the amplification of infection in lymphoid cells and induces the proliferation of infected B cells (21). Infected lymphocytes then carry MMTV to the mammary gland, allowing the virus to be passed to the next generation (1, 13). In addition, it has been demonstrated that MMTV interacts with Toll-like receptor 4 (38), and we have shown that this interaction induces recruitment of dendritic cells (DCs) to the PP and increases the expression of the MMTV cell entry receptor on DCs in vivo (8). We have also reported that DCs are capable of producing infectious virus that can be transmitted to other cell types (11). It has also been reported that MMTV can subvert the host immune system by inducing Toll-like receptor 4-dependent secretion of interleukin-10 by splenic B cells (24).

Superantigen-Activated Regulatory T Cells Inhibit the Migration of Innate Immune Cells and the Differentiation of Naive T Cells

“…It was shown that the early infection of BALB/c mice is governed by the preferential expansion of superantigen-specific CD4 ϩ CD25 ϩ FoxP3 ϩ T cells leading to ϳ25% V␤6 ϩ CD4 ϩ T cells expressing FoxP3 2 wk after infection. These cells had superior Mls-1 a -specific suppressive capacity over CD4 ϩ CD25 ϩ T cells from uninfected mice (49). We have confirmed and extended those findings by demonstrating for the first time in vivo that the superantigenactivated regulatory T cells are able to suppress essential parts of the innate and adaptive immune system, which ultimately leads to the suppressed activation, proliferation, and effector function of T cells, which are not responsive to the superantigen.…”

Regulatory T Cells in Infection

“…More precisely, expansion occurs within a TCR Vb5 CD4 þ Foxp3 þ population, which derived from preexisting ''natural'' Tregs, as there was no conversion of GFP À Foxp3 À T cells transferred to mice immediately prior to infection (Punkosdy et al, 2011). This TCR reacts with the endogenous mouse mammary tumor provirus (MMTV) Mtv9 superantigen, one of several MMTVs which have segregated during inbreeding of laboratory mouse strains (Cohen and Varmus, 1979), and MMTV superantigen-specific Foxp3 þ Tregs have been previously reported (Cabrera et al, 2008). The expansion of regulatory T cell mediated by endogenous retroviral superantigens provides a unique mechanism of immune-evasion following chronic LCMV infection.…”

Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens

“…Not only are pathogen-specific antigens continuously presented during chronic infection, but tissue damage may also result in the presentation of self-antigens. Some studies suggest that Treg that expand after chronic infection can be pathogen specific (13)(14)(15), but these findings are not universal (16). Thus, additional information regarding the mechanism of Treg activation and expansion during chronic infection is important.…”