The knowns and unknowns of latent Mycobacterium tuberculosis infection

Abstract

Humans have been infected with Mycobacterium tuberculosis (Mtb) for thousands of years. While tuberculosis (TB), one of the deadliest infectious diseases, is caused by uncontrolled Mtb infection, over 90% of presumed infected individuals remain asymptomatic and contain Mtb in a latent TB infection (LTBI) without ever developing disease, and some may clear the infection. A small number of heavily Mtb-exposed individuals appear to resist developing traditional LTBI. Because Mtb has mechanisms for intracellular survival and immune evasion, successful control involves all of the arms of the immune system. Here, we focus on immune responses to Mtb in humans and nonhuman primates and discuss new concepts and outline major knowledge gaps in our understanding of LTBI, ranging from the earliest events of exposure and infection to success or failure of Mtb control.

Figure 1. Evasion of T cell recognition versus T cell activation by Mtb-infected antigen-presenting cells.

The paradox of the T cell response to Mtb is that, on the one hand, Mtb antigens, when appropriately processed by an activated antigen-presenting cell, elicit a broad T cell response in a person with LTBI. This involves many T cell subsets responding to a wide range of antigens. These Mtb-activated T cells secrete predominantly Th1 cytokines and chemokines, possess cytotoxic T lymphocyte (CTL) function, and can provide help to B cells. On the other hand, Mtb harbored by macrophages can use a variety of mechanisms to interfere with T cell recognition. These mechanisms have primarily been identified for CD4⁺ T cells and include inhibition of MHC-II antigen processing, antigen escape, and inhibition of T cell receptor–CD3 signaling by Mtb glycolipids, but some may also apply to other T cell subsets. MAIT, mucosal-associated invariant T cell.

Figure 2. Potential protective roles of antibodies and B cells in the lung during both initial Mtb exposure and LTBI.

(A) Antibody isotypes (IgA, IgG, and IgM) could impact Mtb in the lower airways through binding, opsonization, complement activation, and FcR-mediated enhanced phagocytosis and intracellular growth reduction by phagocytes. (B) B cells located in germinal centers of lymphoid tissues could control infection through (i) enhancing antigen presentation to T cells; (ii) production of helper cytokines for T cells; and (iii) generation of antibodies that could modulate innate and adaptive immune responses. (C) Both the presence of B cells and the pro- and antiinflammatory capacities of antibodies could influence the formation of functional granulomas and thereby contribute to the control of Mtb.

Figure 3. Interactions between infected PMNs and macrophages can determine the balance of exacerbating versus protective host responses in LTBI.

Wild-type but not attenuated Mtb drives PMNs into necrotic cell death in a myeloperoxidase-dependent manner. Uptake of Mtb together with necrotic PMNs by resting macrophages further promotes mycobacterial propagation and macrophage necrosis, releasing Mtb for another round of intracellular replication and macrophage death. In contrast, immune activation in LTBI equips macrophages with a potent antimicrobial armamentarium to control and possibly eliminate Mtb. MDSC, myeloid-derived suppressor cells; NET, neutrophil extracellular traps; ^–OCL, hypochlorite.