Working principles in the immune system implied by the "peptidic self" model.

Abstract

The hypothesis that self as well as foreign proteins are processed into peptides and presented by major histocompatibility complex antigens leads to a set of working principles that could govern cellular interactions in immune responses. In particular, "idiopeptides," derived from immunoglobulins and T-cell receptors and recognized by appropriate T cells, are expected to play an important regulatory role. We show here that these speculations fit into a consistent view of the immune system.In the past few years, a remarkable series of experiments has cast light on the function of class I and class II molecules of the major histocompatibility complex (MHC). A growing body of evidence enforces the view that class II MHC molecules bind peptides derived from "processed" (i.e., partially degraded) antigen and expose them on the cell surface (1-3). Importantly, recent experiments indicate that class I MHC molecules could do the same (4-6). The primary function of MHC molecules might thus be to present peptides derived from processed proteins.Assigning a molecular function to MHC molecules is a major accomplishment because they play a pivotal role in regulatory interactions between cells of the immune system. It is well established that the activation and action of various types of T lymphocytes (TH, helper; Ts, suppressor; CTL, cytolytic) requires recognition by T-cell receptors (TCR) of (processed) antigen in association with MHC molecules on the surface of antigen-presenting cells (APCs) or target cells.Under the assumption that the actual function of MHC molecules relies on peptide presentation, we have proposed a logical generalization based on an interpretation of results by Townsend et al. (4, 5)-namely, that self, as well as foreign proteins, can yield peptides presented by MHC molecules (7,8). Cells expressing MHC molecules would thus be permanently coated with a set of distinct peptides somehow reflecting their protein content. For example, somatic cells, most of which express class I MHC molecules, would display myriads of self peptides associated to the latter. APCs (i.e., macrophages, dendritic cells, B cells), which express both class I and class II MHC molecules, would be loaded with antigen-derived peptides in addition to self peptides. Finally, B cells producing a given antibody would expose peptides derived from it, called antibody idiopeptides (designated Ab), while T cells expressing TCR could expose TCR idiopeptides (designated TCR). Therefore, the generalization proposed under our initial peptidic self model (7, 8) leads to two major predictions: (i) the presentation of self peptides by MHC molecules, and (it) the existence of idiopeptides, which, as discussed below, could constitute an important class of regulatory elements. Here, we delineate the implications arising from these premises and show that they lead to a consistent view of the immune system. WORKING PRINCIPLESPresentation by MHC Molecules. So far, little is known about the mechanisms of antigen presentation, but they are likely...

B-lymphoma cells process and present their endogenous immunoglobulin to major histocompatibility complex-restricted T cells.

“…The hypothesis has been supported and extended by later work (6)(7)(8). Similar ideas have recently been proposed by others (9,10), and MHC-restricted T cells specific for idiotypes (11,12) and allotypes (13) have been described. However, it is still unclear whether MHC-restricted T cells recognize processed forms of immunoglobulin exclusively and whether B cells can process their own immunoglobulin.…”

“…Identical sets of precultures were harvested at day 4 and day 5 to ensure that day 5 cocultivated parental cells were exposed to higher concentrations of A2315 than day 4 cocultured antigenic transfectants. The day 10 (25).…”

CD8 T cell priming by B lymphocytes is CD4 help dependent

“…Assuming that T cells against self idiotypes exist in the pool of mature T cells, idiotype-expressing B lymphocytes could activate them provided that CD4 and CD8 T cell tolerance is broken at the same time. Since MHCrestricted CD4 T cells against self idiotype have rarely been reported [46,47], we predict that CD8 T cell responses against idiopeptides [48] are obligatorily rare. In our view, a Th-dependent CD8 T cell activation by B lymphocytes represents a fail-safe mechanism against the inappropriate activation of idiotype-specific CD8 T cells even though variable region framework peptides can bind to MHC class I molecules [49].…”

Creation of H-2 class I epitopes using synthetic peptides: recognition by alloreactive cytotoxic T lymphocytes.

“…Thus, class I as well as class II molecules may function in an analogous manner by binding and presenting antigenic fragments to T lymphocytes. In addition, these results raise the intriguing possibility that class I molecules are normally expressed with peptide bound to them and that not only viral-restricted CTLs, but also alloreactive CTLs, may routinely involve the recognition of such complexes of class I plus peptide (11).…”