Which Cells Are the First to Mount an Attack on the TB Bacterium?

Tuberculosis (TB) remains a major global health challenge, caused by the bacterium Mycobacterium tuberculosis. Once inhaled, the pathogen targets the lungs, where it encounters the body’s immune defenses. TB’s ability to persist within host cells makes understanding the initial immune response crucial for developing better treatments and vaccines.

The first line of defense involves immune cells that act quickly to contain the infection before it spreads.

Defense Barriers in the Lungs

The lungs are constantly exposed to airborne particles, including pathogens like Mycobacterium tuberculosis, requiring specialized defense mechanisms. The first protective layer is the respiratory epithelium, composed of tightly connected epithelial cells that form a physical barrier. Tight junctions reinforce this barrier, limiting pathogen entry while allowing gas exchange. The epithelium also produces antimicrobial peptides such as defensins and cathelicidins, which disrupt bacterial membranes.

The mucociliary clearance system helps expel inhaled particles before they reach deeper tissues. Goblet cells secrete mucus that traps bacteria and debris, while ciliated epithelial cells propel mucus toward the throat, where it is swallowed or expelled. Individuals with impaired mucociliary function, such as those with cystic fibrosis, are more susceptible to respiratory infections, highlighting the importance of this mechanism.

Surfactant proteins, primarily SP-A and SP-D, further enhance lung defenses by binding to bacterial surfaces, aiding immune recognition, and reducing bacterial adherence to lung tissues. Research published in The Journal of Immunology has shown that mice lacking SP-A and SP-D are more susceptible to M. tuberculosis, underscoring their role in early infection control.

First Cellular Responders: Alveolar Macrophages

Once Mycobacterium tuberculosis reaches the alveoli, alveolar macrophages are the first immune cells it encounters. These long-lived phagocytes reside in the lung’s air sacs, continuously surveilling for invaders. Unlike circulating monocytes that migrate upon infection, alveolar macrophages maintain a steady presence. Their primary function is to engulf and degrade pathogens, aided by pattern recognition receptors (PRRs) like toll-like receptors (TLRs) and C-type lectin receptors (CLRs), which detect bacterial components.

Upon recognizing M. tuberculosis, alveolar macrophages initiate phagocytosis, enclosing the bacterium in a phagosome. Normally, the phagosome fuses with lysosomes to form a phagolysosome, where acidic pH, hydrolytic enzymes, and reactive oxygen species (ROS) destroy the pathogen. However, M. tuberculosis has evolved mechanisms to prevent phagosome-lysosome fusion. Studies published in Nature Microbiology show that the bacterium secretes proteins such as PtpA, which interfere with host signaling, allowing it to persist within macrophages.

Beyond pathogen clearance, alveolar macrophages secrete cytokines and chemokines to modulate immune responses. Tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) promote inflammation, while chemokines like CCL2 and CXCL10 recruit additional immune cells. Research in The Journal of Experimental Medicine has shown that mice deficient in TNF-α signaling experience uncontrolled bacterial replication, emphasizing the importance of macrophage-derived cytokines. However, excessive macrophage activation can also contribute to lung tissue damage.

Early Involvement of Neutrophils

As Mycobacterium tuberculosis establishes itself in the lung, neutrophils quickly infiltrate the infection site in response to chemotactic signals. These highly mobile granulocytes, originating from the bone marrow, are drawn to infected tissues by molecules such as interleukin-8 (IL-8) and leukotriene B4.

Once in the lungs, neutrophils employ multiple antimicrobial strategies. Their primary mechanism is phagocytosis, where engulfed bacteria are enclosed in phagosomes that fuse with granules containing neutrophil elastase and myeloperoxidase, generating ROS to degrade bacterial components. However, M. tuberculosis has developed resistance to oxidative stress, limiting this pathway’s effectiveness. Some studies suggest the bacterium can manipulate neutrophil apoptosis, delaying cell death to evade clearance.

Neutrophils also release neutrophil extracellular traps (NETs), web-like structures composed of chromatin and antimicrobial peptides that immobilize pathogens. While NETs can be effective against many bacteria, their role in tuberculosis is complex. Research indicates that M. tuberculosis can trigger excessive NET formation, leading to lung inflammation and tissue damage, potentially worsening disease progression.

Antigen Presentation by Dendritic Cells

Dendritic cells (DCs) play a key role in detecting Mycobacterium tuberculosis and initiating a targeted immune response. Unlike other phagocytes, DCs specialize in processing bacterial components and presenting them to lymphocytes, shaping the immune defense. DCs in the lungs, particularly in the alveolar and interstitial regions, encounter M. tuberculosis through bacterial uptake or by scavenging debris from infected cells. Their surface contains PRRs, including C-type lectin receptors like DC-SIGN, which bind mycobacterial surface molecules such as lipoarabinomannan. This interaction facilitates bacterial internalization and influences immune response activation.

Once internalized, M. tuberculosis is processed within endosomal compartments, where its proteins are broken into peptide fragments. These fragments are then loaded onto major histocompatibility complex (MHC) molecules—MHC class II for CD4+ T cells and MHC class I for CD8+ T cells. However, M. tuberculosis can interfere with endosomal maturation, delaying immune activation. Studies show the bacterium manipulates DC function by suppressing IL-12 secretion and skewing T-cell activation toward an ineffective response.

Adaptive Cell Activation

Once dendritic cells present Mycobacterium tuberculosis antigens, they migrate to lymph nodes to initiate the adaptive immune response. This marks a shift from an immediate reaction to a more specialized defense. T lymphocytes, particularly CD4+ and CD8+ T cells, play a central role in controlling the infection.

CD4+ T cells, or helper T cells, recognize bacterial antigens bound to MHC class II molecules on DCs, triggering differentiation into subsets like Th1 cells, which produce interferon-gamma (IFN-γ). IFN-γ enhances macrophage antimicrobial activity by promoting phagolysosome maturation and reactive nitrogen species production, counteracting bacterial evasion strategies.

CD8+ T cells, recognizing antigens via MHC class I, directly kill infected cells through perforin- and granzyme-mediated cytotoxicity. This mechanism is crucial for eliminating infected macrophages, preventing M. tuberculosis from using them as refuges. Research in The Journal of Clinical Investigation shows that individuals with weakened CD8+ T cell responses have higher bacterial loads, emphasizing their role in infection control. Additionally, memory T cells develop during this process, providing long-term immunity for faster responses upon future exposure. However, M. tuberculosis has evolved mechanisms to dampen T cell activation, such as inhibiting antigen presentation and inducing regulatory T cells that suppress immune activity, complicating efforts to achieve sterilizing immunity.