Age-associated changes in intrathymic B cell function

Abstract

Abstract Autoimmune disease affects approximately 3% of the U.S. population and is the leading cause of death among young and middle-aged women. Susceptibility to autoimmune disease generally increases with age in both sexes; however, mechanisms linking aging and increased susceptibility are incompletely understood. One hallmark of the aging immune system is atrophy of the thymus, the primary site of T lymphocyte generation. We recently showed that in addition to size, critical thymic functions are lost with age, including expression of tissue restricted self-antigen (TRA) genes. Thymic TRA expression allows clonal deletion of potentially auto-reactive T cells, and loss of TRA expression during aging represents a potential mechanism for age-associated increases in autoimmunity. Until recently, only epithelial cells were known to express TRAs within the thymus, but it is now clear that IgM-IgD-intrathymic B lymphocytes can also be induced to express Aire (Autoimmune Regulator), a factor critical for TRA expression, as well as downstream Aire-dependent TRAs. Here, we find that B cell frequency increases 5-fold in the aged murine thymus, concomitant with a shift from an IgM-IgD-to an IgM+IgD+ phenotype. Using next-generation RNA sequencing, we show significant decreases in Aire and TRA gene expression in aged intrathymic B cells. Our findings indicate that age-associated changes in intrathymic B cells inhibit their ability to negatively select auto-reactive T cells, revealing a novel potential mechanism linking aging with increased susceptibility to autoimmune disease.