Alveolar macrophages shape tuberculosis susceptibility by delaying protective immunity

Abstract

Effective control of Mycobacterium tuberculosis (Mtb) infection requires timely activation and accumulation of CD4⁺ T cells in the lungs, yet the factors delaying this response remain unclear. Here we show that alveolar macrophages (AMs) delay CD4⁺ T cell priming by retaining Mtb within the alveolar lumen, limiting other myeloid cells access to the bacteria. This defect is more pronounced in susceptible C3HeB/FeJ mice than in C57BL/6 mice and arises from reduced IL-1β and GM-CSF production, which impair the migration of AMs to the lung parenchyma. Targeting AMs accelerates the activation of the adaptive immune response but fails to promote bacterial control over the chronic phase of infection due to neutrophils interference on CD4⁺ T cell function. Crucially, sequential depletion of AMs and neutrophils restores CD4⁺ T cell function and enhances infection control. These findings uncover a novel bottleneck in tuberculosis immunity and suggest that targeting AMs may accelerate adaptive immunity but overcoming local inflammatory constraints may be necessary to sustain infection control.