Diverse Repertoire of the MHC Class II-Peptide Complexes Is Required for Presentation of Viral Superantigens

Abstract

Among other features, peptides affect MHC class II molecules, causing changes in the binding of bacterial superantigens (b-Sag). Whether peptides can alter binding of viral superantigens (v-Sag) to MHC class II was not known. Here we addressed the question of whether mutations limiting the diversity of peptides bound by the MHC class II molecules influenced the presentation of v-Sag and, subsequently, the life cycle of the mouse mammary tumor virus (MMTV). T cells reactive to v-Sag were found in mice lacking DM molecules as well as in AbEp-transgenic mice in which MHC class II binding grooves were predominantly occupied by an invariant chain fragment or Eα52–68 peptide, respectively. APCs from the mutant mice failed to present v-Sag, as determined by the lack of Sag-specific T cell activation, Sag-induced T cell deletion, and by the aborted MMTV infection. In contrast, mice that express I-Ab with a variety of bound peptides presented v-Sag and were susceptible to MMTV infection. Comparison of v-Sag and b-Sag presentation by the same mutant cells suggested that presentation of v-Sag had requirements similar to that for presentation of toxic shock syndrome toxin-1. Thus, MHC class II peptide repertoire is critical for recognition of v-Sag by the T cells and affects the outcome of infection with a retrovirus.

A Defective Viral Superantigen-Presenting Phenotype in HLA-DR Transfectants Is Corrected by CIITA

“…The presentation of vSAgs was suggested to be dependent on a diverse repertoire of class II-bound peptides (71). Because a fraction of the class II molecules in HeLa and DAP cells are bound with large polypeptides in the absence of Ii, we verified whether HeLa cells express some SDS-stable compact heterodimers containing short peptides and migrating at 55 kDa on immunoblots (10,46,99).…”

“…Their observations imply an exclusive association of the vSAg with mature, peptide-loaded, SDS-stable class II molecules. Accordingly, it was later proposed that successful presentation of vSAg7 is conditional to the existence of a diverse, class II-bound peptide repertoire (71). Indeed, endogenous vSAg-induced T cell deletion was not taking place in modified mice expressing class II molecules almost exclusively loaded with CLIP (DM knockout (KO)) or loaded with a covalently linked peptide (E␣ [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] ).…”

Molecular and Cellular Basis of the Retrovirus Resistance in I/LnJ Mice

“…Biologically active MMTV(LA) virions were incubated with F(abЈ) 2 or with total IgGs and then injected into the footpads of uninfected BALB/cJ mice. This route of MMTV infection induces a vigorous localized immune reaction during which the numbers of SAg-cognate T cells increase in draining popliteal lymph nodes (38,39). MMTV(LA) is a natural mixture of three different viruses a Numbers in table body indicate number of mice producing anti-MMTV polyvalent Abs per total number of recipient mice.…”

Peptide Specificity of Thymic Selection of CD4+CD25+ T Cells

“…Thymocytes (A) or lymph node cells (B) from indicated mice were stained and analyzed as described in Fig. 2. expressing A b bound with many endogenous peptides (22). To examine whether CD4 ϩ CD25 ϩ T cells are eligible to deletion by conventional A b /peptide complex, we used mice that express the A b Ep63K complex.…”