Engagement of the B lymphocyte antigen receptor induces presentation of intrinsic immunoglobulin peptides on major histocompatibility complex class II molecules

Abstract

By means of the clonotypic variable region, the immunoglobulin (Ig) is a tumor-specific antigen on B cell neoplasms. We report that engagement of the B cell antigen receptor (BcR) promotes presentation of peptides derived from the B cell's intrinsic Ig to major histocompatibility complex (MHC) class II-restricted T cells. Thus, anti-Ig endowed normal, ex vivo B lymphocytes from H-2d, Ig constant heavy chain allotype b (IgCHb) mice with the capacity to stimulate an I-Ad-restricted T cell clone which recognizes the gamma 2ab 435-451 allopeptide. The corresponding self gamma 2aa peptide is cryptic and 6000-fold less antigenic than the gamma 2ab allopeptide. Even so, the syngeneic B cell lymphoma A20 which expresses surface(s) IgG2aa, was also recognized by the T cells after BcR ligation. Thus, anti-Ig triggered the disclosure of a cryptic tumor antigen determinant. We propose that autoantigens, by engaging the BcR of self-reactive B cells, induce presentation of intrinsic Ig peptides to which the T helper cell (Th) repertoire is not tolerant. In this way, B cells with anti-self potential may be activated without Th recognition of nominal autoantigen.

T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

“…Finally, peptides from the BCR V region may provide an avenue of T cell help to autoreactive B cells. The BCR V region is promising in this regard because of the enormous diversity encompassed by V region peptides and because such peptides can be self-presented in class II MHC by activated B cells, which presumably are dependent upon T cell help (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). We refer to this potential avenue of help to autoreactive B cells as the receptor presentation hypothesis (35).…”

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of spleen cells from BALB/c (I‐A d , IgC H a ,) and BXSB (I‐A b , IgC H b ,) failed to stimulate B5 (K. Bartnes, unpublished).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.…”

“…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 . Thus, B5 is insensitive to B7‐mediated signals, 14 the interactions of the γ2a b determinant with the B5 antigen receptor and I‐A d have been characterized in detail, 10,15 , 16 and the B5‐defined epitope is among the predominant determinants generated by processing of IgG2a b (refs 10,11; K. Bartnes, unpublished). 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).…”

Advances in T-Cell Epitope Engineering

“…Many synthetic subunits can be substituted for proteogenic amino acids to impede proteolysis. These include D-amino acids (Bartnes et al, 1997), β-amino acids (Webb et al, 2005), psi-bonded amino acids (Stemmer et al, 1999), and the shifting of the R group by one atom to create poly- N -substituted glycines (peptoids) where the side chains are appended to the nitrogen atom of the peptide backbone (Gocke et al, 2009). …”