Lymph nodes are like security checkpoints for the body. They are constantly surveilling cells and signals flowing in from nearby tissues, always on the lookout for dangerous invaders. Never knowing where the next threat may strike, they are located throughout the body so no tissue goes unprotected. Security guards, in the form of immune cells, stay at the ready to intervene swiftly when danger, such as a pathogen, is detected.
Immune interventions in the lymph node are coordinated, cascading events. Each immune cell has a specialized role in the battle against infection. Antigen-presenting cells inform T cells to the nature of the threat. Different helper T cells in turn help fight off infection by activating infected cells or mobilizing B cells to secrete antibodies. Inflammatory molecular signals put everyone on alert. The lymph node becomes the command center for both detecting and mounting adaptive immune responses against pathogens throughout the body. But what happens when the lymph node itself becomes infected?
Infection with the bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis, the deadliest infectious disease worldwide, killing over 1 million people each year. Although infection begins in the lungs, it can spread to the lymph nodes and beyond. Mtb infection is notoriously difficult to clear. The bacteria can live dormant for years, and in the lungs, can form lesions that block out immune cells and antibiotics.
The teams of Dr. Michael Gerner in the University of Washington Department of Immunology and Dr. Kevin Urdahl at Seattle Children’s Research Institute are interested in understanding how lymph node infection contributes to Mtb persistence. Dr. Gerner explained, “Mycobacterium tuberculosis is primarily viewed as a respiratory pathogen, yet it frequently persists long-term in lung-draining lymph nodes, even when pulmonary lesions appear cleared. This presents a fundamental immunological paradox: how can the body’s primary command center for launching T cell immunity also act as a safe haven for pathogen persistence?”
In a study recently published in Immunity, researchers from the Gerner and Urdahl labs investigated this paradox by analyzing the spatial and temporal immune dynamics in lung-draining lymph nodes in a mouse model of Mtb infection. They sought to detail both how Mtb infection spreads to lymph nodes and how it evades immune responses there.
The researchers applied multiple approaches, including flow cytometry, confocal microscopy, and single cell RNA sequencing, to assess the activation and location of immune cell populations over the course of infection. They found that initially, Mtb travels from the lung to lymph nodes by infecting two types of migratory immune cells: conventional dendritic cells (cDCs) and monocytes. In lymph nodes, infected dendritic cells induce clustering and activate Mtb-specific T cells. Over the first 15 days of infection, the lymph node mounts a robust immune response to Mtb.
Then a shift occurs. The burden of Mtb infection increases as the immune architecture within the lymph node changes. Abnormal aggregates of monocyte-derived cells form and immune activation diminishes. Dr. Gerner explained, “Over time, cDC migration wanes and the lymph node becomes dominated by heavily infected, monocyte-derived aggregates where Mtb replicates locally. Surprisingly, despite expressing classic inflammatory and microbicidal pathways, these monocyte aggregates fail to clear Mtb and activate neighboring Mtb-specific T cells, allowing the bacteria to evade immune surveillance and persist.”
Thus, transient immune responses in the lymph node give way to tissue remodeling and metabolic changes that create a niche for Mtb to persist. And persist it does. The team found that infected, monocyte-derived aggregates in the lymph node remain for at least 110 days after infection, while T cell immune impairment continues for at least 50 days. Dr. Gerner commented, “The inability of T cells to recognize these aggregates highlight the pathogen’s advanced strategies for immune evasion.”
The researchers are optimistic that understanding how the lymph node environment shifts during infection may open new avenues for drug development targeting persistently infected cells. In particular, they hypothesize that because the infected monocyte-derived aggregates look different than the infected cDCs that initially activate T cells, immune surveillance becomes ineffective once the lymph node remodels. Drs. Gerner and Urdahl commented, “Moving forward, our research aims to decipher the pathogenic and antigen shifts within these persistent monocytic niches. By identifying non-classical or stress-associated Mtb responses, we hope to inform next-generation TB vaccines and immunotherapies capable of granting 'sight' back to the host immune system to eliminate persistent bacterial reservoirs.”
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Michael Gerner contributed to this research.
The spotlighted research was funded by the National Institutes of Health and the Center for Global Infectious Disease Research at Seattle Children's Research Institute.
Shamskhou EA, Duffy FJ, Cross LM, Plumlee CR, Gern BH, Barrett HW, Diercks AH, Cohen SB, Sivakumar R, Aitchison JD, Ganusov VV, Urdahl KB, Gerner MY. 2026. Monocytic niches escape T cell surveillance and promote Mycobacterium tuberculosis persistence in lymph nodes. Immunity. doi: 10.1016/j.immuni.2026.05.017
Science Spotlight writer Ashley Person is a PhD candidate in the Cohn lab in the Vaccine and Infectious Disease Division at Fred Hutch. She studies how HIV-infected cells persist over time in people living with HIV on long term treatment.