Superantigen-reactive CD4+ T cells are required to stimulate B cells after infection with mouse mammary tumor virus.

Abstract

SummarySuperantigens are defined by their ability to stimulate a large fraction of T cells via interaction with the T cell receptor (TCR) V/3 domain. Endogenous superantigens, classically termed minor lymphocyte-stimulating (Mls) antigens, were recently identified as products of open reading flames (ORF) in integrated proviral copies of mouse mammary tumor virus (MMTV). We have described an infectious MMTV homologue of the classical endogenous superantigen Mls-1 ~ (Mtv-7). The ORF molecules of both the endogenous Mtv-7 and the infectious MMTV(SW) interact with T cells expressing the TCR VB6, 7, 8.1, and 9 domains. Furthermore, the COOH termini of their ORF molecules, thought to confer TCR specificity, are very similar. Since successful transport of MMTV from the site of infection in the gut to the mammary gland depends on a functional immune system, we were interested in determining the early events after and requirements for MMTV infection. We show that MMTV(SW) infection induces a massive response of V~6 + CD4 + T cells, which interact with the viral ORE Concomitantly, we observed a B cell response and differentiation that depends on both the presence and stimulation of the superantigen-reactive T cells. Furthermore, we show that B cells are the main target of the initial MMTV infection as judged by the presence of the reverse-transcribed viral genome and ORF transcripts. Thus, we suggest that MMTV infection of B cells leads to ORF-mediated B-T cell interaction, which maintains and possibly amplifies viral infection. M inor lymphocyte-stimulating (Mls) antigens are encodedby an open reading frame (ORF) z in the 3' LTR of endogenous mouse mammary tumor virus (MMTV) (1-3). They stimulate a large proportion of T cells due to the fact that T cell reactivity to Mls antigens is determined by the usage of the V segment of the TCR B chain (4, 5). The classical (and strongest) Mls determinant, Mls-1 ', which interacts with T cells expressing VB6, 7, 8.1, and 9 elements (4-7), is encoded by the ORF of the Mtv-7 proviral locus (8). We have recently found an exogenous (infectious) MMTV, MMTV(SW), with properties of Mls-1 ' (9). The ORF molecules of Mtv-7 and MMTV(SW) display an almost identical amino acid sequence, particularly in COOH termini implied to confer TCR VB specificity. In fact, both endogenous Mtv-7 and infectious MMTV(SW) interact with the same TCR VB elements. In an MMTV-infected host, ORF-reactive T cells are deleted from both the thymic and peripheral T cell pool, although at a considerably slower rate than after expression of the endogenous Mtv-7 (Mls-l') locus. Furthermore, injection of adult mice with MMTV(SW) leads to expansion of V~6 + CD4 + T cells similar to that observed after injection of . A functional immune system seems to be a prerequisite for successful transport of MMTV to the mammary gland after neonatal infection through the gut mucosa. Thus, thymectomy, absence of T cells (in nude mice), or deletion of the ORF-reactive T cells prevent virus transmission to the next generation (lO-12).Whil...

Clonal Isolation of Different Strains of Mouse Mammary Tumor Virus-Like DNA Sequences from Both the Breast Tumors and Non-Hodgkin’s Lymphomas of Individual Patients Diagnosed with Both Malignancies

“…The MMTV-infected B cells express the MMTV sag on their surface that, in turn, recognizes and stimulates T cells with a V␤ sequence corresponding to the hypervariable region of the sag protein. Different strains of MMTV will stimulate different T-cell receptors, and increased T-cell expansion allows, in turn, for increased B-cell expansion supplying more cells for MMTV infection (55). The MMTV-like beta retrovirus in primary biliary cirrhosis patients appears to be preferentially located in lymphoid tissues with a limited viral abundance in liver where the end organ damage occurs in this disease (42).…”

TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts

“…30 MMTV (SW) encodes a V␤6-specific superantigen. Synchronized plasmablasts were isolated from the draining popliteal lymph nodes 6 days after infection, and purified with phycoerythrin-conjugated antimouse CD138 (BD Biosciences, San Jose, CA) and anti-phycoerythrin magnetic beads (Miltenyi Biotech).…”

“…To specifically address the survival effect of BAFF and APRIL on antibody secreting cells, mice were infected with MMTV and synchronized plasmablasts were isolated from the draining lymph node 6 days after infection. 30 Alternatively, mice were immunized with tetanus toxoid, and plasmablasts were isolated from spleens at the peak of the booster response. Purified plasmablasts were cultured for 2 days in vitro, in the presence or absence of BAFF or APRIL, and the number of viable, antibodysecreting cells was quantified by ELISPOT.…”

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

“…The infected B cells receive cognate SAgdependent T cell help from the primed T cells. SAg recognition is determined by the expression of SAg-reactive T cell receptor V␤ elements, and up to 30% of peripheral T cells can react with such infected SAg-presenting cells (2,3). The SAg response is comparable to classical T cell-B cell interactions and leads to both follicular and extrafollicular B cell responses in the lymph nodes (LN) draining the site of injection.…”