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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(+) CD25(+) T cells from the PP of infected mice preferentially suppress the proliferative response of T cells to SAg-expressing antigen-presenting cells ex vivo. We investigated the influence of the depletion of CD25(+) cells at different stages of the infection. When CD25(+) cells were depleted before MMTV infection, an increase in the number of PP SAg-cognate Foxp3(-) T cells was found at day 6 of infection. Since the SAg response is associated with viral amplification, the possibility exists that T(reg) cells attenuate the increase in viral load at the beginning of the infection. In contrast, depletion of CD25(+) cells once the initial SAg response has developed caused a lower viral load, suggesting that at later stages T(reg) cells may favor viral persistence. Thus, our results indicated that T(reg) cells play an important and complex role during MMTV infection.

SUBMITTER: Cabrera G

PROVIDER: S-EPMC2493342 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Early increases in superantigen-specific Foxp3+ regulatory T cells during mouse mammary tumor virus infection.

Cabrera Gabriel G Burzyn Dalia D Mundiñano Juliana J Courreges M Cecilia MC Camicia Gabriela G Lorenzo Daniela D Costa Héctor H Ross Susan R SR Nepomnaschy Irene I Piazzon Isabel I

Journal of virology 20080521 15

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(+) CD25(+) T cells from the PP of infected mice preferentially suppress the pr ...[more]

PMID: 18495774

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Project description:Breast cancer vaccines composed of antigens identified by serological analysis of cDNA expression libraries (SEREX) induce antigen specific immune responses in patients but have had disappointing clinical benefits. While many attempts to modify the adjuvants and vaccine method have been tried, one issue not addressed was whether the SEREX tumor-associated antigens identified from late stages of disease were ideal targets. We questioned in the transgenic TgMMTV-neu mouse model whether the antigen repertoire is distinct between early and late stage breast cancer and whether the antigens identified via SEREX from transgenic mice with early or late stage tumors would elicit differential anti-tumor effects to address this question. Three early stage antigens, Pdhx, Stk39, and Otud6B, were identified from a SEREX screen of mice prior to development of palpable lesions. Formulated into a vaccine, each early antigen inhibited tumor growth (p?<?0.0001). The antigens identified from mice with late stage tumors (Swap70, Gsn, and Arhgef2) were unable to inhibit tumor growth when used as vaccines (for example Gsn p?=?0.26). Each of the three early stage antigens were essential for tumor survival in syngeneic mouse tumor cells and in human breast cancer cell lines across breast cancer subtypes. Silencing protein expression of the early antigens increased apoptosis (p?<?0.0001 for all antigens in mouse and p?<?0.05 for all antigens in human triple negative breast cancer) and decreased survival (p?<?0.0001 for all antigens in mouse and human triple negative and HER2 positive breast cancer). Overexpression of the early stage antigens in women with breast cancer predicted worse prognosis (p?=?0.03) while overexpression of late stage antigens did not impact prognosis (p?=?0.09). These data suggest that antigens expressed earlier in breast tumor development and functionally relevant to breast tumor growth may be more effective targets for therapeutic breast cancer vaccines than antigens identified in later disease.

Dataset Information

Early increases in superantigen-specific Foxp3+ regulatory T cells during mouse mammary tumor virus infection.

Publications

Early increases in superantigen-specific Foxp3+ regulatory T cells during mouse mammary tumor virus infection.

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