Late Infection - T Regulatory Cells
A subpopulation of T cells known as T regulatory (Treg) cells further mediates host immune responses to infectious diseases. During infectious disease including mycobacterial infections Tregs play a dual role: they benefit the host by limiting immune-mediated pathology and also facilitate chronic pathogen persistence by reducing effector immunity and clearance of infection.
During acute infection, the beneficial role of Tregs seems to predominate by facilitating optimal antigen presentation and lymphocyte recirculation. However, while Treg cells successfully control excessive immune responses in the host to preserve homeostasis, as a consequence this may lead to enhanced pathogen survival and in the case of mycobacterial infection, longterm pathogen persistence (Belkaid and Tarbell, 2009). Several types of Tregs are currently recognized and can be thymus-derived, peripheral tissue-derived or from unknown origin. Another distinction is natural vs adaptive Tregs. In mice, several characteristic phenotypes have been described but unique markers are lacking in nonmurine species. Tregs are preferably defined by a combination of markers such as forkhead box P3 (FoxP3) transcription factor and CD25, along with demonstration of suppressive activity. The latter is important since other non-Treg populations may also express ‘Treg markers' (Boer etal., 2015). It has been noted that bovine CD4+ CD25+ FoxP3+ T cells lack functional suppressive activity, while γδ T-cell subsets do show a suppressive functional phenotype, suggesting that γδ T cells may represent true Tregs in cattle (Hoek etal., 2009; Guzman etal., 2014). Key regulatory cytokines such as IL-10 have been associated with reduced secretion of IFN-γ by PBMCs isolated from cows with subclinical paratuberculosis (de Almeida et al., 2008). Further, depletion of IL-10-producing T cells from the PBMCs of infected cattle revealed the characteristic phenotype of Tregs, CD4+ CD25+. Previously, a highly significant reduction in IFN-γ production was noted with the addition of exogenous IL-10 and TGF-β to PBMC cultures, with and without the presence of live MAP, an effect that was independent of the infection status of the cows (Khalifeh and Stabel, 2004a). Interestingly, an increase in IL-10 secretion was observed after the addition of TGF-β to cell cultures. Similarly, exogenous IL-10 and TGF-β suppressed the production of IFN-γ by PBMCs from TB skin-testpositive individuals, with greater suppression in the presence of both IL-10 and TGF-β (Othieno et al., 1999). The least suppression was noted with the addition of IL-10 alone, indicating that TGF-β mediates the suppression of IFN-γ both directly and indirectly through IL-10. A comprehensive review of Tregs in paratuberculosis suggested that additional mechanisms for immune regulation may exist, especially in cattle (Coussens et al., 2012). Recent studies with M. tuberculosis have indicated the presence and importance of myeloid regulatory cells (MRCs), also termed monocytic myeloid-derived suppressor cells (M-MDSCs) (Dorhoi and Du Plessis,2018). These populations include regulatory DCs, as well as regulatory and alternatively activated macrophages (M2-like macrophages). These phagocytes are capable of pathogen internalization and persistence, while exerting localized suppressive activity of T cells and induction of Treg cells. Patients with active tuberculosis or after recent TB treatment had an increased frequency of myeloid-derived suppressor cells leading to reduced proinflammatory T-cell function (du Plessis et al., 2013). Immunohistochemical staining of mid-ileal tissue from cattle has also indicated a predominance of M2 antiinflammatory macrophages coordinating with T cells in advanced stages of bovine paratuberculosis. While this may help limit inflammatory tissue damage within the host, it may also lead to a failure to control bacterial replication leading to increased bacterial burden within the tissue (Jenvey et al., 2019).
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