Tertiary Lymphoid Structures in Tuberculosis: Persistence, Protection, and Pathology

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a major public health burden responsible for over a million deaths each year. A deeper understanding of the mechanisms that balance protective immunity and immunopathology is essential for developing more effective therapeutics. This review focuses on the dynamic interplay between CD4⁺ T cells and B cells in the lung, with an emphasis on their interactions in tertiary lymphoid structures (TLS). TLS are immune cell aggregates that arise in inflamed, nonlymphoid tissues, range from loosely to highly organized clusters, and serve as localized hubs for immune cell interaction, activation, and diversification. Drawing on insights from other disease contexts, including infections, cancer, and chronic inflammatory conditions, we examine the molecular signals and cellular interactions involved in TLS formation, maintenance, and function during Mtb infection. Additionally, we explore the anatomical and functional integration of TLS with the lymphatic and vascular systems, and how this spatial organization may influence bacterial persistence and dissemination. Clarifying the functional role of TLS in TB—whether they support protective immunity, contribute to lung pathology, or both—could inform novel approaches to modulate local immune responses and improve TB disease outcomes.