Early Infection - Macrophage- T-Cell Interaction
Macrophages activated by mycobacteria produce a number of cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α and IL-12 (Wang et al., 1999; Hope et al., 2004).
Infection with MAP initiates the upregulation of the aforementioned cytokines, in addition to other proinflammatory cytokines, IL-6, IL-8 and IL-10 (Adams and Czuprynski, 1994; Coussens et al., 2004; Weiss et al., 2004). Presentation of major histocompatibility complex (MHC) class II antigens on the surface of the macrophage, along with IL-1 secretion, results in the activation of T cells. Activated T cells produce IL-2, which aids in the clonal expansion of specific CD4+ T helper cells and CD8+ cytolyticT cells. Upon activation, the naive CD4+ Tcell can differentiate into several subtypes including Th1, Th2 or Th17 cells, based upon the nature of the antigen presented and other factors in the microenvironment. Differentiation of the CD4+ T-cell population is skewed towards a Th1 T-cell subpopulation in the early stages of MAP infection, characterized by the secretion of the Th1- associated cytokines, IFN-γ, IL-2 and TNF-α (Burrells et al., 1998; Stabel, 2000). The strong bias towards a Th1-mediated immune response in the early stages of infection is dominated by the key effector cytokine, IFN-γ. Studies have reported higher expression of IFN-γ in PBMCs of cattle infected with MAP (Coussens et al., 2003, 2004; Khalifeh and Stabel, 2004a), and this was correlated with higher levels of IFN-γ secreted by PBMCs isolated from animals in the subclinical or early stages of infection, whether it be natural or experimental (Stabel, 2000; Waters et al., 2003; Khalifeh and Stabel, 2004a). In sheep, the early appearance of robust IFN-γ responses was associated with the control of disease progression to a more advanced stage (de Silva et al., 2013, 2018). IFN-γ plays a crucial role in the activation of T cells and macrophages, DC maturation, upregulation of MHC class I and II molecules, and production of reactive oxygen and nitrogen species by macrophages (Delvig et al., 2002; Shankar et al., 2003). CD4+ T cells appear to be the primary source of IFN-γ in mycobacterial, including MAP, infections, but CD8+ and γδ T cells also produce IFN-γ. Quantities of IFN-γ secreted by γδ T cells in response to MAP antigens appear to be lower than amounts produced by CD4+ or CD8+ T cells, but this may be antigen-dependent (Shin et al., 2005). γδ T cells accumulate at the site of infection prior to CD4+ T-cell arrival, secrete significant amounts of IFN-γ (Plattner et al., 2013) and induce intracellular killing of MAP in infected macrophages (Baquero and Plattner, 2017); in particular, the WC1.1+ subset appears to influence disease control in the early stages of infection (Albarrak et al., 2018).IFN-γ not only induces the secretion of IL- 12 by APCs, resulting in Th1 induction via a paracrine pathway, but also acts to directly augment Th1 polarization via an autocrine mechanism that does not involve IL-12 (Teixeira et al., 2005). Together with a downregulation of MHC class II-mediated antigen presentation pathways that mediate CD4+ T-cell responses, there is an upregulation of MHC class I gene expression indicating a switch to CD8+ T-cell responses early in MAP infection of cattle (Purdie et al., 2012).
Similarly in sheep, a lack of protection against MAP infection is associated with early dysfunction of CD4+ T-cell, B-cell and γδ T-cell responses, but not CD8+ T-cell responses (de Silva et al., 2015).
IL-12 and IL-18 are both important mediators of anti-mycobacterial immunity and appear to induce IFN-γ synergistically through activation of Th1 cells (Kohno et al., 199 7; O'Donnell et al., 1999; Sugawara et al., 1999). Although they share some biological properties, these two cytokines utilize different signal transduction pathways in the induction of IFN-γ, suggesting a unique regulatory process in T-cell activation (Nembrini et al., 2006).
Very little information has been published on the roles of IL-12 and IL- 18 in MAP infections to date. Gene expression studies have generated variable results (Coussens et al., 2004; Tanaka et al., 2005; Smeed et al., 2007). Interestingly, when used as an adjuvant for paratuberculosis vaccines, IL-12 has not demonstrated increased IFN-γ secretion or reduced MAP colonization in tissues of vaccinated animals (Uzonna et al., 2003; Kathaperumal et al., 2008). This is in contrast to a study that demonstrated that co-immunization with a plasmid containing IL-12 and M. tuberculosis Ag85B enhanced IFN-γ secretion and protection against M. tuberculosis infection (Triccas et al., 2002). It has been suggested that induction of a strong T-cell receptor (TCR) response is responsible for the majority of IFN-γ production and that IL-12 and IL-18 play supporting roles, perhaps becoming more critical when a TCR signal is weak or misaligned (Nembrini et al., 2006). Since mycobacterial cell wall components are highly antigenic, it is likely that IL-12 and IL-18 are both used by the host as compensatory mediators of IFN-γ production.Early immune responses are pivotal in determining eventual disease outcome in MAP infection and, in sheep, the magnitude of early IFN-γ responses appears to be an important factor (de Silva etal., 2013, 2018).
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