The Developmental and Functional Implications of Age-Associated B Cells (ABCs) Across Tissue Microenvironments

Age-associated B cells (ABCs) are a dynamic B cell subset whose identity, development, and function are fundamentally shaped by the tissue microenvironments in which they reside. Primarily defined by expression of CD11c and T-bet, ABCs arise across diverse contexts, including aging, infection, autoimmunity, and cancer, yet exhibit striking heterogeneity that reflects the distinct signals present in each tissue niche. While the core generative cues of TLR7/9 activation, IFN-γ, IL-21, and BCR stimulation are common, the local tissue environment dictates how these signals are integrated and which functional properties are ultimately expressed. In infectious environments, altered splenic structure, peripheral tissue inflammation, and organ-specific cytokine gradients influence context-dependent ABC phenotypes with unique localization and effector characteristics. In autoimmune diseases, target organ microenvironments provide the TLR ligands, cytokines, and cellular interactions that sustain local ABC expansion and pathogenic activity. Similarly, in the tumor microenvironment, ABCs are shaped by tertiary lymphoid structures and chronic inflammatory signals that can shift their function between pro-inflammatory and immunosuppressive states. This review explores how tissue microenvironments influence ABC biology in infections, autoimmunity, and cancer, highlighting critical implications for understanding disease mechanisms and developing targeted therapeutic strategies.