Understanding the heterogeneous population of age-associated B cells and their contributions to autoimmunity and immune response to pathogens

In humans and mice, susceptibility to infections and autoimmunity increases with age due to age-associated changes in innate and adaptive immune responses. Aged innate cells are also less active, leading to decreased naïve T-and B-cell responses. Aging innate cells contribute to an overall heightened inflammatory environment. Naïve T and B cells undergo cell-intrinsic age-related changes that result in reduced effector and memory responses. However, previously established B-and T-cell memory responses persist with age. One dramatic change is the appearance of a newly recognized population of age-associated B cells (ABCs) that has a unique cluster of differentiation (CD)21^–CD23^– phenotype. Here, we discuss the discovery and origins of the naïve phenotype immunoglobulin (Ig)D⁺ versus activated CD11c⁺T-bet⁺ ABCs, with a focus on protective and pathogenic properties. In humans and mice, antigen-experienced CD11c⁺T-bet⁺ ABCs increase with autoimmunity and appear in response to bacterial and viral infections. However, our analyses indicate that CD21^–CD23^– ABCs include a resting, naïve, progenitor ABC population that expresses IgD. Similar to generation of CD11c⁺T-bet⁺ ABCs, naïve ABC response to pathogens depends on toll-like receptor stimulation, making this a key feature of ABC activation. Here, we put forward a potential developmental map of distinct subsets from putative naïve ABCs. We suggest that defining signals that can harness the naïve ABC response may contribute to protection against pathogens in the elderly. CD11c⁺T-bet⁺ ABCs may be useful targets for therapeutic strategies to counter autoimmunity.