Tertiary lymphoid tissue develops during normal aging in mice and humans

Aging has multifaceted effects on the immune system in the context of systemic responses to specific vaccines and pathogens, but how aging affects tissue-specific immunity is not well defined. Chronic bladder inflammation is highly prevalent in older women, but mechanisms by which aging promotes these pathologies remain unknown. Here we report distinct, age associated changes to the immune compartment in the otherwise normal female (but not in male) mouse urinary bladder and parallel changes in older women with chronic bladder inflammation. In aged mice, the bladder epithelium became more permeable, and the homeostatic immune landscape shifted from a limited, innate immune-predominant surveillance to an inflammatory, adaptive immune predominant environment. Strikingly, lymphoid cells were organized into tertiary lymphoid tissues, hereafter named bladder tertiary lymphoid tissue (bTLT). Analogous bTLTs were found in older women, many of whom had a history of recurrent urinary tract infection (UTI). Aged mice responded poorly to experimental UTI, experiencing spontaneous recurrences at higher rates than young mice. However, bTLT formation was dependent on aging and independent of infection. Furthermore, bTLTs in aged mice played a role in de novo antibody responses and urinary IgA production by recruitment of naive B cells that form germinal centers and mature into IgA-secreting plasma cells. Finally, TNFα was a key driver of bTLT formation, as aged TNFα-/- mice lacked bTLTs. Both aged TNFα-/- and wild type mice exhibited increased bladder permeability, suggesting that epithelial dysfunction may be an upstream mediator of chronic, age-associated bladder inflammation. Thus, bTLTs arise as a function of age and may underlie chronic, age-associated bladder inflammation. Our model establishes a platform for further investigation of age-association tissue inflammation and translation to new treatment strategies.