Endogenous Ligands Selecting T Cells Expressing Particular Vβ Elements

Abstract

It has recently become clear that the minor lymphocyte stimulatory antigens (Mls) and other endogenous ligands which lead to the partial or total deletion of T cells bearing particular V beta segments are encoded by mouse mammary tumor virus (MMTV). We review here the genetic analyses of multiple V beta 11 and V beta 3 deletion ligands and demonstrate the involvement of MMTV in all examples. Several features of Mls and the V beta 11/V beta 3 deleting ligands identify them as members of the superantigen family. Bacterial superantigens are known to bind both MHC class II and the TCR in regions distinct from conventional peptide antigens. Within the MMTV genome, the 3' LTR has been identified as encoding superantigen function. We present data demonstrating that in vitro translation identifies the major product of the open reading frame (ORF) within the 3' LTR as a type II integral membrane glycoprotein. It is proposed that the type II membrane glycoprotein interacts with MHC and TCR in a manner analogous to the bacterial superantigens and distinct from conventional peptide antigen. Several unanswered questions regarding superantigen action remain; what determines total or partial deletion? How is Mls transferred between cells? These questions are addressed in the discussion.

T‐Cell Receptor Repertoire Selection by Mouse Mammary Tumor Viruses and MHC Molecules

“…and see Tomonari et al, this volume) has been found to produce a deletion phenotype similar to Mtv-7 and -43, as does an exogenous MMTV transferred accidentally during embryo transfer to BALB/c stock (Held et al 1992). Interestingly, Mtv-44 also affects selection of T cells expressing V;ff3, previously found to be affected by several Mtv integrations (Fairchild et al 1991, Tomonari et al, 1992a, 1992c, Tomonari & Fairchild 1992, Pullen et al 1992). The identification of the Mtv-encoded product responsible for the Mis and TCR V^ deletion effects came from studies using transgenic mice and transfectants used to stimulate appropriate TCR V^-expressing hybridomas, Acha-Orbea et al (1991) found that not only mice transgenic for the entire GR-Mtv-2 genome, but also those transgenic for sequences limited to the open reading frame (ORF) within the LTR of this Mtv deleted V^14+ T cells.…”

“…Tomonari MacDonald et al 1988 Benoist & Mathis 1989Tomonari & Fairchild 1992Tomonari et al 1992Tomonari et al 1992Liao et al 1989Blackman et al 1989Zuniga-Pflucker et al 1989Tomonari 1992 The feature shared by each of the observations derived from backcross analysis is that all mice inheriting the selecting MHC molecules show the same increased level of cells expressing the selected TCR V^ (Tomonari & Fairchild 1992, Tomonari et al 1992b, Tomonari 1992. This monophasic distribution is in contrast to the findings with negative selection, in which amongst mice sharing the same H-2 haplotype there is a bi-or tri-phasic distribution of the levels of cells expressing the selected TCR V^ , Tomonari & Fairchild 1991, Dyson et al 1991, Fairchild et al 1991, 1992, Fairchild & Tomonari 1992, Tomonari et al 1992a). The selection of V^6^ CD8^ T cells by various MHC class I alleles shows evidence of a hierarchy of affinity for this V/?…”

“…Direct characterization of the ORF product has been somewhat limited with the detection only of the product of a partially deleted LTR present in the EL-4 lymphoma line (Racevskis 1986). Additionally, our laboratory, using anti-peptide antibodies has produced limited results by immune precipitation of the LTR-derived products of endogenous Mtvs from lymphoid cell hnes capable of inducing T-cell hybridoma stimulation (Tomonari et al 1992a). However, various in vitro translation approaches have been used in an attempt to express the protein and to define it at a biochemical level.…”

Influence of Viral Superantigens on Vβ‐and Vα Specific Positive and Negative Selection

“…References Fairchild et al 1991: Frankel et al 1991Tomonari et al 1992bFrankel et al 1991;Tomonari el al. 1992bTomonari et al 1992bFairchild et al 1993Fairchild et al 1992Frankel et al 1991Frankel et al 1991Fairchild et al 1992Ixe & Eicher 1990 Lee Frankel et al 1991This paper Lee & Eicher 1990;This paper Fairchild et al 199! ;Frankel et al 1991;Tomonari et al 1992bFrankel el al.…”

META-Controlled env-Initiated Transcripts Encoding Superantigens of Murine Mtv29 and Mtv7 and Their Possible Role in B Cell Lymphomagenesis

“…14,15) were purchased from The Jackson Laboratory (Bar Harbor, ME). (SJL ϫ SWR)F 1 mice were bred in the animal facilities of New York University School of Medicine (New York, NY).…”