Transition From Early to Late Infection - T-Cell Subpopulations

Activated CD4+, CD8+ and γδ T-cell subpopu­lations are recognized sources of IFN-γ, but CD4+ T cells appear to be most highly reactive to mycobacterial antigens in the early stage of infection (Flynn et al., 1993).

2017). The role that CD8+ T cells fulfil may be influenced by the maturity of the host immune system or the number of exposures to a particu­lar pathogen.

Since γδ T cells produce IFN-γ in response to mycobacteria, it is believed that they contribute to the protection of the host early in the infec­tion process, in a way that is distinct from that of γ T cells (Kaufmann, 1996). In a MAP challenge study, TCR-α-deficient mice had higher levels of MAP colonization in their tissues compared with TCR-δ-deficient mice or C57BL/6 control mice (Stabel and Ackermann, 2002). Lesions were located predominantly in the liver or the ileum, depending upon the period of infection, and lesion scores were higher for TCR-α-deficient mice. Further suggestion of a unique role for γδ T cells stems from evidence that during experi­mental infection with intracellular pathogens such as Listeria and M. avium subsp. avium, TCR- γδ-deficient mice formed atypical lesions in their tissues instead of the granulomatous lesions seen in wild-type mice (Mombaerts et al., 1993; Saunders et al., 1998). Similarly, Tanaka et al. (2000) presented evidence of reduced granu­lomatous lesions in TCR-γδ-deficient mice after challenge with MAP. These studies suggest that γδ T cells play a role in clearance of the pathogen after infection, which either harmonizes with or compensates for γ T cells.

More recently, the role that Th17 cells play in cellular immunity to mycobacterial infections has come into focus. Th17 cells are characterized by cell surface expression of CD4 and the ability to secrete IL-17 and IL-22.

2011). It is plausible that Th17-type immune responses become more established as disease progresses in subclinical cattle and this likely re­flects the inability to control intracellular MAP infection.

Less studied but none the less proving to be critical checkpoints in modulation of host immu­nity in early and late stages of T-cell responsive­ness, respectively, are the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) pathways (Buchbinder and Desai, 2016). Increased cell surface expression of CTLA-4 in effector cells leads to inhibition of T-cell prolif­eration and survival, with suppressive functions of regulatory T cells (Tregs) correlated to their constitutive expression of CTLA-4. PD-1 expres­sion is characteristic of ‘exhausted’ T cells and is associated with chronic infections. The pres­ence of CTLA-4+ CD4+ T cells was significantly higher in naturally infected cows in the subclini- cal stage of disease compared with clinical cows, suggesting an engagement in limiting T-cell ef­fector function as disease progresses (Leite et al., 2015). In later subclinical stages of bovine in­fection, MAP-specific T-cell exhaustion has been observed to be partially mediated via upregula­tion of PD-1 and lymphocyte activation gene-3 (LAG-3) (Okagawa et al., 2016).

In an effort to understand the dynamic disease progression in MAP infection, math­ematical models were developed using datasets from well-characterized naturally infected cattle (Magombedze et al., 2014). Using the assump­tions that Th1 responses are driven by intracel­lular bacteria and that Th2 responses are driven by extracellular bacteria, and that these immune responses are not cross-suppressive, this model supports previous experimental studies (Stabel, 2000) to predict that the Th1 to Th2 switch is a result of disease progression. Although such models are provocative, they are hampered by the complexity of immune responses and chang­es in the microenvironment at the site of infec­tion that are not completely understood as yet.

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