Native IgG2a^b is barely antigenic to major histocompatibility complexclass II‐restricted T cells owing to inefficient internalization by professionalantigen‐presenting cells

Abstract

Peptide epitopes derived from immunoglobulin variable regions represent tumour-specific antigens on B-cell neoplasms and can be recognized by syngeneic, major histocompatibility complex (MHC) class II-restricted T cells. Immunoglobulin peptide/MHC class II complexes may also be involved in autoimmunity and CD4+ T-cell-mediated B-cell regulation. Thus, the IgG2a(b) H-chain allopeptide gamma2a(b) 435-451 presented on I-Ad mimics the epitope implicated in herpes simplex virus-induced autoimmune stromal keratitis and is the target of T helper 1 (Th1) clones that suppress IgG2a(b) production in vivo. We here report that spleen and thymus cells constitutively present the autologous gamma2a(b) epitope to a gamma2a(b) 435-451/I-A(d) reactive T-cell hybridoma as a function of the animal housing conditions (specific pathogen-free or not) and the serum levels of IgG2a(b). Constitutive presentation in the spleen was predominantly performed by dendritic cells. Whereas spleen cells poorly presented native IgG2a(b) to a gamma2a(b) 435-451/I-A(d) reactive T-cell hybridoma, IgG2a(b) in the form of immune complexes were presented > 200-fold more efficiently owing to internalization via low-affinity FcgammaR on macrophages. The antigenicity could also be improved by homotypic aggregation and by targeting IgG2a(b) to complement receptors on the A20 B-cell lymphoma. Mice without detectable IgG2a(b)-containing immune complexes typically exhibited minimal constitutive presentation. Nevertheless, native IgG2a(b) can sensitize antigen-presenting cells in vivo, as mice that were devoid of immune complexes and carried an IgG2a(b)-producing tumour did present constitutively, even at physiological IgG2a(b) serum levels. Whereas the amounts of IgG released from most B-cell lymphomas may be too low to allow spontaneous priming of tumour-specific MHC class II-restricted T cells, administration of tumour immunoglobulin in aggregated form might improve the efficacy of idiotype vaccination.

T cells from multiple sclerosis patients recognize immunoglobulin G from cerebrospinal fluid

“…Aggregation of IgG during affinity purification could enhance the uptake and presentation by APC. 24 Alternatively, acid treatment may mimic post-translational modifications induced by enzymes in vivo , and render the altered proteins more immunogenic. 25 T cells from the CNS of animals with experimental autoimmune encephalomyelitis have a more stringent specificity and restriction pattern than circulating T cells.…”

Cerebrospinal fluid T cell clones from patients with multiple sclerosis: recognition of idiotopes on monoclonal IgG secreted by autologous cerebrospinal fluid B cells

“…This could be due to maturation of dendritic cells [53], or to enhanced internalization of aggregated IgG via FccR on APC [54,55]. To demonstrate the effect of heat aggregation, the responses to heat-aggregated and non-aggregated autologous CSF mAb were compared (Fig.…”

Genes predisposing to autoimmunity augment constitutive major histocompatibility complex class II‐associated presentation of the self‐antigen IgG2abin vivo

“…Furthermore, constitutive presentation is independent of maturation of APC and intercellular antigen transfer in vitro , as cells that were paraformaldehyde fixed immediately after preparation were stimulatory, and a co‐culture of spleen cells from BALB/c (I‐A d , IgC H a ,) and BXSB (I‐A b , IgC H b ,) failed to stimulate B5 (K. Bartnes, unpublished). Confirming the poor antigenicity of native IgG2a b in vitro , constitutive presentation was weak or absent in specific pathogen‐free (SPF) healthy animals, which had low levels of circulating IgG2a b –C3 complexes and not more than a few hundred µg/ml of serum IgG2a b 13,14 . In contrast, spleen cells from mice reared under less rigorous microbial control regularly elicited strong B5 hybridoma responses, 9,13 demonstrating a profound influence of environmental factors on the constitutive presentation of the IgG2a b self‐antigen.…”

“…Confirming the poor antigenicity of native IgG2a b in vitro , constitutive presentation was weak or absent in specific pathogen‐free (SPF) healthy animals, which had low levels of circulating IgG2a b –C3 complexes and not more than a few hundred µg/ml of serum IgG2a b 13,14 . In contrast, spleen cells from mice reared under less rigorous microbial control regularly elicited strong B5 hybridoma responses, 9,13 demonstrating a profound influence of environmental factors on the constitutive presentation of the IgG2a b self‐antigen. To the extent that these findings apply to IgG in general, analyses of constitutive presentation of IgG2a b to the γ2a b /I‐A d ‐reactive T‐cell hybridoma, B5, may be useful in elucidating the factors that determine IgG peptide presentation and thus provide information relevant both in the immunopathogenesis of HSV‐induced autoimmune keratitis and for designing clonotypic immunoglobulin vaccines against lymphomas.…”

“… 12 However, native IgG2a b is a surprisingly weak antigen for I‐A d ‐restricted T cells, as 700 IgG2a b molecules (1400 epitopes) were required to generate the antigenic equivalent of a single γ2a b peptide. 13 Internalization by antigen‐presenting cells (APC) was limiting, as targeting to FcγR or complement receptors (CR) strikingly augmented T‐cell responses. Notably, the γ2a b 435–451/I‐A d reactive T‐cell hybridoma, B5, responds to APC from IgC H b , I‐A d mice in the absence of exogenous IgG2a b and should represent a useful, quantitative probe for analysing constitutive γ2a b /I‐A d presentation in vivo .…”