Investigating mechanisms restricting responsiveness of B cells specific for foreign antigens

Abstract

Abstract In order to prevent antibody-mediated autoimmunity, B cells reactive against self-antigens are subjected to tolerance mechanisms including induction of a state of restricted functionality termed anergy. We hypothesize that anergy also restricts responsiveness of B cells specific for foreign antigens due to B cell receptors (BCR) cross-reactivity with endogenously expressed molecules. Using a previously published antigen-specific enrichment strategy, we have shown that 60–80% of antigen-specific B cells fail to respond to antigen immunization. While some of this poor responsiveness is likely a result of low affinity, many B cells binding high levels of antigen are found within the non-responding population. A broadly-inclusive marker for self-reactivity in mice with an intact polyclonal B cell repertoire has been identified using the orphan nuclear receptor Nur77, known to be up-regulated downstream of BCR signaling. Using Nur77-eGFP reporter mice, we have found that populations of B cells specific for non-self antigens display a range of baseline Nur77 expression similar to that of total B cells, perhaps indicating a similar extent of self-antigen recognition. Coordinately, we have found that antigen-specific naive B cells expressing low levels of Nur77 are more responsive to immunization than their counterparts expressing high levels of Nur77. These data suggest that responsiveness of naive B cells specific for foreign antigens is restricted by cross-reactivity with self-antigens. Our results could lend a unique perspective to the paradigmatic definition of B cell anergy and offer an accession to immunogen design as the principle factor governing protective humoral immune responses following vaccination.