T cell recognition of endogenous IgG 2a expressed in B lymphoma cells

199

137

Antigen-presenting B-lymphoma cells were transfected with the gene encoding the immunoglobulin A2 light chain of MOPC315 cells (A2315). The A2 chain is expressed on the cell surface of the transfectants together with the endogenous heavy chain. (4) and that this recognition was under H-2-linked immune response (Ir) gene control (5). The hypothesis has been supported and extended by later work (6-8). 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.To test this directly we have used recently established T-cell clones specific for an idiotope of A2315 in the context of the I-Ed MHC antigen (7,8). These clones, like the T cells studied in vivo before (4, 5), recognize an idiotypic determinant on A2315 around amino acid positions 94, 95, and 96 (7, 8

supporting

confidence: 76%

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

Weiß

Bogen

1989

199

137

“…The majority of virally encoded proteins in the cytosolic compartment are processed and presented by the infected cells as MHC class I-peptide complexes for interaction with CD8 T cells (32). However, in some cases, endogeously derived peptides also can be routed to endocytic class II MHC compartments (14,33,34). Our previous (14) and current studies demonstrate that retrovirally transduced foreign protein inframe with ␥ heavy chain can induce MHC class II-restricted tolerance, manifested by hyporesponsiveness to that protein at both the CD4 T cell level and antibody production.…”

Section: Discussionmentioning

confidence: 99%

Induction of hyporesponsiveness to intact foreign protein via retroviral-mediated gene expression: The IgG scaffold is important for induction and maintenance of immune hyporesponsiveness

Kang

Melo

Deng

et al. 1999

IgG molecules can be highly tolerogenic carriers for associated antigens. Previously, we reported that recipients of bone marrow or lipopolysaccharide-stimulated B-cell blasts, both of which were retrovirally gene-transferred with an immunodominant peptide in-frame with the variable region of a murine IgG heavy chain, were rendered profoundly unresponsive to that epitope. To further investigate whether tolerance to larger molecules can be achieved via this approach and whether the IgG scaffold is important for induction and maintenance of immunological tolerance, we engineered two retroviral constructs encoding the cI repressor (MBAE-1-102 and MBAE-1-102-IgG) for gene transfer. Our results show that recipients of bone marrow or peripheral B cells, transduced with the MBAE-1-102-IgG recombinant, are hyporesponsive to p1-102. In addition, the self-IgG scaffold enhanced the induction and maintenance of such an immune hyporesponsiveness. Thus, our studies demonstrate that in vivo-expressed IgG heavy chain fusion protein can be processed and presented on the appropriate MHC class II, resulting in hyporesponsiveness to that antigen and offering an additional therapeutic approach to autoimmune diseases. Individuals normally develop tolerance to self-constituents during the development of the immune system. Tolerance induction, however, is a lifelong process and also must occur extrathymically (1). Moreover, the maintenance of this unresponsive state requires the persistence of antigen and continued induction in adults (2). The failure to discriminate between immunological self and nonself components leads to the clinical manifestations of autoimmunity. A number of experimental procedures have been proposed to induce tolerance to autoantigens and therefore to prevent and͞or reverse autoimmune diseases (3-5), although tolerance induction and maintenance in mature animals has proven difficult. Hence, novel methods need to be developed to promote tolerance induction in immunocompetent adults and to express the tolerogen in multipotential hematopoietic compartments for persistence of tolerogen and long-term maintenance of tolerance.Peptide fragments of multideterminant antigens can be divided into three main groups: dominant, subdominant, and cryptic epitopes (6-8). An immunodominant epitope is a peptide fragment specifically processed by antigen-presenting cells from a larger, multideterminant antigen and varies individually as a function of its MHC. Such an epitope is capable of binding to the MHC molecule, and this peptide͞MHC complex then is recognized by the T-cell repertoire (6, 7). Subdominant epitopes are the determinants that can stimulate native protein primed cells to proliferate, but less than dominant epitopes or the whole protein (7,8). In contrast, cryptic determinants are rarely revealed during antigen processing and therefore fail to activate T cells when the native antigen is used as immunogen (7,8). However, these hidden determinants might play a role in pathogenic autoimmune responses. One of the...

“…The predicted existence of idiopeptides playing a regulatory role in immune responses, although hypothetical, fits the conclusions of several reports. It seems that IgG2a allotypes require a presentation process to elicit a T-cell response (16). X2 light (L)-chain idiotopes and chemically synthesized peptides have a similar effect in a syngeneic T-cell response (17), and a MHC-linked gene control of helper T cells specific for variable-region heavy-chain (VH) determinants has been demonstrated (18).…”

Section: Working Principlesmentioning

confidence: 99%

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

Kourilsky¹,

Chaouat²,

Rabourdin–Combe³

et al. 1987

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...