Immune cell interactions in tuberculosis

Abstract

Despite having been identified as the organism that causes tuberculosis in 1882, Mycobacterium tuberculosis has managed to still evade our understanding of the protective immune response against it, defying the development of an effective vaccine. Technology and novel experimental models have revealed much new knowledge, particularly with respect to the heterogeneity of the bacillus and the host response. This review focuses on certain immunological elements that have recently yielded exciting data and highlights the importance of taking a holistic approach to understanding the interaction of M. tuberculosis with the many host cells that contribute to the development of protective immunity.

Figure 1.. The heterogeneous M. tuberculosis-host interaction in granulomas determine infection and disease outcomes

Cellular immunological and scRNA-seq analyses of granulomas, together with imaging and the use of barcoded bacilli, have revealed a high degree of heterogeneity of the granulomatous response among infected non-human primates and humans. In Mtb infection of naive hosts (left panel), the spectrum of heterogeneity spans resolution in restrictive granulomas, i.e., those that kill or limit replication of Mtb, to progression in permissive granulomas with increased bacterial growth and limited killing and dissemination to form new granulomas, representing the extremes on a continuum of disease states. Granulomas harbor a wide variety of immune cells and immunological factors (left and right panels), whose interactions likely govern whether the lesions progress or regress. The significance of the ability of specific cellular and immunological parameters of a granuloma in determining disease outcomes is seen in subjects of immunization-challenge studies (right panel), which can reflect vaccine efficacies. The granulomas developed upon challenge with virulent Mtb after immunization with highly protective vaccines such as i.v. BCG, which affords near sterilizing protection, are absent or smaller relative to unimmunized subjects and contain fewer or no bacilli (right panel). In addition, the lung parenchyma of non-human primates subjected to the i.v. BCG immunization-challenge model harbors CD4 T cells and CD8 T cells, and the airway is populated with both T cells and antibodies, suggesting an important role for these immunological elements in mediating vaccine-engendered protection against Mtb (right panel).

Figure 2.. The interaction between lung macrophages and M. tuberculosis shapes the host response to the tubercle bacillus and influences the development of drug tolerance

In a mammalian host, alveolar macrophages (AM) of embryonic origin populate the air space prior to birth. (1) The AM population is self-renewing and represents the host cell that Mtb apparently targets primarily upon entering into the lung alveolar space. (2) Mtb-infected AM, through IL-1 receptor (IL-1R) signaling-dependent mechanisms (2), translocate from the alveolar space into the lung interstitium (3), serving as the vehicle that carries bacilli into the parenchyma. The translocation of infected AM is dependent on IL-1R, MyD88, and ASC in a macrophage-extrinsic fashion through non-hematopoietic cells. Translocated Mtb-infected AM multiplies in the interstitium, forming cellular aggregates (4), followed by recruitment from the vasculature (5) of neutrophils and monocyte-derived macrophages (6), which are then infected. The parenchyma of the lungs contains interstitial macrophages (IM), which are of bone marrow origin (7) and can be infected with Mtb (8). IM are a highly heterogeneous population, consisting of multiple subsets that interact with Mtb differentially, raising the possibility that distinct macrophage sub-populations may contribute to granuloma heterogeneity (Figure 1). One functional characteristic that reflects subset heterogeneity of AM and IM macrophage populations is the levels of stress these phagocytes imposed on Mtb, as assessed by fitness reporter mycobacterial strains (9). Mouse studies have shown that the AM and IM lineages display distinct metabolism (possibly pre-programed as a result of their different origins [1 and 7] and niche [2 and 8)] that differentially regulates replication of intracellular bacilli.) These cellular parameters translate to AM being more permissive for Mtb growth compared with IM. The levels of stress encountered by Mtb intracellularly can promote drug tolerance (10), an intermediate state conducive to the development of drug resistance. Permissive macrophages are depicted by higher number of paler bacilli in the phagosomes, while restrictive macrophages are those with lower number and darker bacilli in the vacuoles. The darker color of the bacilli denotes higher levels of macrophage-imposed intracellular stress.

Figure 3.. The B cell and humoral immune response to Mtb

The host response to Mtb begins with the presentation of Mtb antigens (Ag) by antigen-presenting cells to cognate CD4⁺ and CD8⁺ T cells, initiating the development of specific T cell lineages (1). In parallel, naive B cells interact with Mtb component (2), which results in the development of activated B cells. The initial encounters of T cells and B cells with Mtb Ag are an essential first step that leads to the formation in the germinal center of T follicular helper cells (Tfh) and germinal center B cells (3), which interaction is critical for the generation of memory B cells (4), and long-lived antibody (Ab)-producing plasma cells (5). Memory B cells can react rapidly in response to Mtb antigenic challenge, and the plasma cells (5), which produce high quality Ab (6), are critical for the generation and maintenance of serological memory. These latter two components are pivotal to the development of a robust and effective humoral immune response to microbes and Ab-based vaccines. In addition, Mtb Ag-activated B cells (7) can produce soluble factors such as pro-inflammatory and anti-inflammatory cytokines to modulate the development of anti-tuberculosis immunity (8). Additionally, the multifunctional B cells can contribute to the regulation of the immune response to Mtb via other effector functions such as the presentation of Ag to T cells (9). Together, the capacity of B cells to present Ag and to produce cytokines and Mtb-specific Ab can contribute significantly to the regulation of the granulomatous response during Mtb infection. These properties of B cells, in turn, play a role in mediating interaction between B cell and humoral immunity to the broad gamut of immune cells present in the tuberculous granuloma (Figure 1) to determine infection and disease outcomes, granuloma heterogeneity, and the levels of immunopathology (10). Of the major effector functions of B cell and humoral immunity (6, 8, and 9), the role of Ab in modulating anti-tuberculosis immune responses is perhaps the best studied. Specific humoral responses are associated with distinct infection and disease outcomes in human subjects. These are likely related to diverse Ab-mediated effector functions (11) as regulated by differential glycosylation of the Fc fragment of immunoglobulins (Ig) and the distinct functionality of the range of Ab isotypes. The interaction between the Fc of Ab and Fc receptors (FcR) can significantly regulate Ab-mediated effector functions of Ig to (1) modulate opsonophagocytosis, (2) block invasion of the pathogen, (3) enhance dendritic cell (DC) function via engagement of immune complex (IC) by DC to augment T cell responses, (4) mediate Ab-dependent cell-mediated cytotoxicity (ADCC) by targeting NK cells, and (5) Ab-dependent cell-mediated phagocytosis (ADCP) by targeting macrophages and neutrophils. These Ab-mediated effector functions, in turn, modulate infection and disease outcomes, granuloma heterogeneity, and the levels of immunopathology (12).