Elsevier

Advances in Immunology

Volume 65, 1997, Pages 139-243
Advances in Immunology

Mouse Mammary Tumor Virus: Immunological Interplays between Virus and Host *

https://doi.org/10.1016/S0065-2776(08)60743-9Get rights and content

Introduction

It took nearly 100 years from the first description of mammary tumors in wild mice (Crisp, 1854) to the discovery that an extrachromosomal factor was responsible for the high incidence of mammary carcinomas in susceptible mouse strains (Lathrop and Loeb, 1918, Staff of the Roscoe B. Jackson Memorial Laboratory, 1933, Koretweg, 1934). Soon thereafter it was realized that this factor was transmitted maternally via milk to the offspring (Bittner, 1936). However, more time was required to convince researchers that the agent responsible for tumor formation was a retrovirus (Bryan et al., 1942, Bittner, 1948, Passey et al., 1950, Dmochovski and Grey, 1957, Bernhard, 1958). One of the reasons for the skepticism was the finding that tumor-free mouse strains were found to be infected with such retroviruses in the mammary gland. The presence and role of endogenous viruses was not known yet. Despite the difficulty of obtaining large quantities of virus (mostly from mouse milk or in lower amounts from supernatants of mammary tumor cell cultures) and the long incubation times for biological readouts (for cancer development, often more than 1 year), mouse mammary tumor virus (MMTV) has been in the center of cancer research from 1940 to the late 1970s. Only the most important older articles will be cited in this review. The work of this period was already extensively reviewed (Nandi and McGrath, 1973, Bentvelzen and Hilgers, 1980).

Interest into MMTV was reawakened when it was found that MMTV represented the solution to a more than 20-year-old immunological puzzle. In the early 1970s Festenstein (1973) described that mixed lymphocyte reactions between different strains of mice could lead to extremely strong reactions even when the two mouse strains involved were major histocompatibility complex (MHC) compatible. He called the antigens responsible for this effect minor lymphocyte stimulating (Mls) antigens. It took over 20 years of frustrating trials to generate antibodies and to characterize biochemically and immunologically the nature of these Mls antigens. Finally it was shown that this effect was encoded by an open reading frame (orf) with previously unclear functions encoded by endogenous MMTV proviruses (for nomenclature see below) (Acha-Orbea et al., 1991, Choi et al., 1991, Woodland et al., 1991b). These proviruses can be found in all commonly used mouse strains and in the majority of wild mice. Nearly all of them encode a functional superantigen (SAg).

SAgs were originally described as bacterial antigens capable of binding to different MHC class II but not MHC class I molecules and of interacting with a large proportion of T cells sharing a T cell receptor (TCR) Vβ element (Janeway et al., 1989, Kappler et al., 1989a, White et al., 1989). Because the numbers of Vβ elements are limited (25 for mice and 50 100 for humans), a large proportion (130%) of T cells will be triggered by a given SAg. This compares with 1 in 104 106 T cells for a classical peptide-MHC complex; hence the name SAg.

To date, SAgs have been described in bacteria (Staphylococci, Streptococci, Mycobacteria, Yersinia, and Mycoplasma), retroviruses (MMTV), other viruses (rabies, CMV, and EBV), protozoa, and even in plants (for reviews see Janeway et al., 1989, Marrack and Kappler, 1990, Acha-Orbea, 1993, Kotzin et al., 1993, Scherer et al., 1993, Acha-Orbea and MacDonald, 1995, Fleischer et al., 1995, or specific references in section VI). Despite significant structural differences between these proteins, they all share the above definition in binding MHC class II molecules and interacting polyclonally with T cells sharing a TCR Vβ element.

For MMTV it was clearly shown that the role of these SAgs is to allow a much more efficient infection (Held et al., 1993b). Their role for bacteria is less clear. Most likely, the presence of a SAg allows a slight advantage in the maintenance or propagation of the infection although the results are not completely clear yet (Rott and Fleischer, 1994).

What makes SAgs interesting for immunologists and virologists is their profound effect on the immune system and the ability to follow the reacting T cells in vivo as well as in vitro with antibodies specific for TCR Vβ elements. The characterization of SAg-induced immune responses gives insights into thymic and peripheral tolerance induction, unresponsiveness (anergy), antigen presentation, immune response, TB collaboration, as well as virus host interaction. Some of the older key findings as well as the newer developments will be discussed.

Section snippets

Mouse Mammary Tumor Virus

Like all the members of the retrovirus family, MMTV encodes gag, pol, and env molecules in its 8.5-kb RNA genome (see Fig. 1). To synthesize these proteins the retroviral RNA has to be reverse transcribed and integrated into the genome of the host cell. What makes MMTV special is a long orf in the 3’ long terminal repeat (LTR). It encodes a SAg and is required for completion of the retroviral life cycle.

As will be discussed, infectious MMTV requires an intact immune system for completion of its

Structure of the SAg Protein

One of the distinctive features of SAgs is the requirement for MHC class II expressing SAg presenting cells and the recognition of this complex by T cells bearing SAg-reactive TCR Vβ elements. Clear evidence for bacterial as well as rabies virus SAgs binding with high affinities to MHC class II molecules exists (Fraser, 1989, Herrmann et al., 1989, Mollick et al., 1989, Lafon et al., 1992). Careful mutational analysis and cocrystals between bacterial SAgs and human DR molecules have been

Immune Response to MMTV

The immune response to MMTV can be divided into three major phases. Within hours after virus uptake a T cell- and SAg-independent B cell activation occurs (see Section IV,A). After 1 or 2 days the infected B cells present the SAg on their cell surface, which leads to a SAg-dependent T–B collaboration. This second phase leads to proliferation and differentiation of both T and B cells very similar to classical T–B interactions and peaks between days 4 and 6 (see Section IV,B). The third phase is

T and B Cell Response to Endogenous Mtv

The majority of experiments with endogenous Mtv SAgs were done before the role of SAgs was known. The earlier results are only introduced briefly to help understand the previous nomenclatures. Thereafter, they are summarized based on the recent knowledge of the role of endogenous Mtv proviruses in this process. For more complete lists on the earlier literature see Festenstein (1973), Abe and Hodes (1989), and Janeway (1991).

Comparison with Other SAgs

SAgs have been described in a variety of microorganisms. Some of their features are summarized in Table IV. Many bacterial strains produce SAgs. The best known are the staphylococcal enterotoxins, which are the causative agents of food poisoning (SEA, SEB, SEC1-3, SED, and SEE) and the toxic shock syndrome (TSST-1) (Fleischer and Schrezenmeier, 1988, Janeway et al., 1989, White et al., 1989, Marrack and Kappler, 1990). Other bacterial SAgs are found in streptococci (SPE-A, -B, and -C) (Imanishi

LIFE CYCLE OF MMTV

The life cycle of mouse mammary tumor virus is characterized by an unusual dependence on the immune system. This dependence starts right after uptake of the virus-containing milk by the neonatal mice; Infection is exclusively detected among the B cells of the Peyer’s patches, and in the absence of B cells no productive infection is seen. Binding of virus particles to B cells by themselves possibly induces the B lymphocytes to enter cell cycle and allows the integration of the viral DNA into the

ACKNOWLEDGMENTS

We thank Anne Wilson, Ulrich Beutner, and Daniela Finke for the suggestions and the critical reading of the manuscript.

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    *

    This article was accepted for publication on 1 October 1996.

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