Selective immunosuppression by administration of major histocompatibility complex class II-binding peptides. II. Preventive inhibition of primary and secondary in vivo antibody responses.

Abstract

SummaryThe self-mouse lysozyme peptide corresponding to residues 46-62 (ML46-62) binds to the major histocompatibility complex (MHC) class II molecules I-A k and it selectively inhibits, when coinjected with antigen, priming of I-Ak-restricted, antigen-specific T cells. We demonstrate that administration of ML46-62 also inhibits in vivo antibody responses induced by I-A krestricted T helper cells. ML46-62 is able to prevent the primary anti-hen egg white lysozyme (HEL) antibody response induced by the entire HEL molecule in B10.A(4R) mice, expressing only I-A k molecules, but not in mice of H-2 a haplotype. ML46-62 also strongly decreases, in B10.A(4R) mice, the antibody response to ribonuclease A, a protein antigen unrelated to the MHC blocker, indicating that MHC blockade is the mechanism leading to inhibition of antibody response. This is further supported by the concomitant decrease, in vivo, of complex formation between immunodominant HEL peptides and I-A k molecules, preventing I-AL-restricted T cell induction. Administration of ML46-62 after antigen priming does not affect ongoing antibody responses, as expected from MHC blockade. A single injection of ML46-62 at the time of protein antigen priming precludes not only the primary, but also the secondary antibody response to a subsequent challenge with soluble protein, even when the challenge is performed several months after priming. Coinjection of antigen and MHC antagonist inhibits production of all antibody isotypes equally well, suggesting that MHC class II blockade affects both Thl-and Th2-type T helper cells. Therefore, these results indicate that administration of MHC class II-binding peptides can efficiently and selectively prevent the induction of T cell-dependent primary and secondary in vivo antibody responses by blocking antigen presentation to class II-restricted T helper cells. p ~eptides bound to class II MHC molecules on the surface of APCs are the ligands for antigen-specific receptors of CD4 + T cells (1). Each MHC class II molecule can bind different peptides, indicating that the interaction between peptides and class II molecules exhibits a low degree of selectivity (2). One consequence of the broad-range specificity ofpeptide-MHC interactions is that peptides of different sequences may compete for presentation by the same MHC molecule to T lymphocytes.Peptide competition for antigen presentation has been demonstrated in vitro, by showing that antigens binding to the same MHC molecules can compete with each other for presentation to T cells (3-6). A direct correlation has been demonstrated between the capacity of a peptide to bind to purified MHC class II molecules and its ability to compete for presentation of antigenic peptides binding to the same class II molecules (7,8). Peptide competition for the MHC class II binding site also occurs in vivo. This has been demonstrated first by competition between self-and non-self peptides for T cell activation, showing that T cell responses to antigenic peptides can be inhibited by coinjection o...

Dendritic cells but not B cells present antigenic complexes to class II-restricted T cells after administration of protein in adjuvant.

“…The Antigen-presenting Activity in Immune LNC Is Restricted to the Low Buoyant Density Population. We have previously shown that APC in draining lymph nodes from mice immunized subcutaneously with HEL in adjuvant display antigenic complexes formed in vivo between peptides derived from HEL processing and class II molecules (19,20). After immunization with HEL in IFA or CFA, antigenic complexes are readily detectable on lymph node APC from day 2 to 14 after immunization (not shown).…”

Differences in the Reactivity of CD4+ T‐Cell Lines Generated against Free Versus Nucleosome‐Bound SV40 Large T Antigen

“…However, T cells selected by immunization and in vitro clonal expansion driven by T‐ag in SVT2nuc would be expected to respond at least as well to SVT2nuc as free T‐ag. The weaker proliferative responses of SVT2nuc immune T cells may be explained by limited presentation of processed T‐ag peptides due to competition with peptides derived from other proteins present in SVT2nuc [28–30]. This competition between T‐ag‐derived peptides and other peptides could, in turn, have limited the activation and clonal expansion of T‐ag‐specific T cells in vivo and in vitro .…”

Down-regulation of antigen-specific antibody production by TCR antagonist peptidesin vivo

“…Previous studies have demonstrated that blockade of MHC binding could inhibit T cell activation and Ab production in response to stimulation by antigenic peptides in vivo [22,23]. As shown in Figs.…”