Late Infection - T-Cell Responses

The progression of paratuberculosis from a subclinical to clinical state is associated with a switch from Th1 to Th2 immune response. The production of Th2 regulatory cytokines, IL-4, IL-5 and IL-10, supports a humoral immune response characterized by the expansion of B lymphocytes, immunoglobulin secretion and control of Th1-mediated responses.

Both IL-4 and IL-10 have been noted to play specific roles in the suppression of IFN-γ production by CD4+ Th1 cells (Peleman et al., 1989; Ito et al., 1999). There is little evidence to suggest a specific role for IL-4 in mediating protective immunity against MAP, as expression of IL-4 in tissues does not appear to be associated with the infection status of the host animal (Sweeney et al., 1998; Coussens et al., 2004). However, two reports have documented reduced expression of IL-4 in PBMC from subclinically and clinically infected cows as compared with control cows after stimulation with MAP (Coussens etal., 2004; Karcher et al., 2008). In contrast, IL-4 secretion by PBMCs stimulated with a whole-cell sonicate of MAP was greater in clinical cows compared with control and subclinical cows, fitting the paradigm shift to Th2-mediated immunity in clinical disease (Karcher et al., 2008).

IL-10 seems to play a more significant role in mycobacterial infections in general, and specifically during MAP infection. An upregulation of IL-10 in tissues, including ileum, mesenteric lymph nodes and cultured PBMCs, from naturally infected cattle and sheep with paratuberculosis has been observed (Coussens et al., 2004; Khalifeh and Stabel, 2004b; Smeed et al., 2007). Increased expression of IL-10 was observed in bovine monocyte-derived macrophages infected with MAP as compared with M. avium subsp. avium (Weiss et al., 2002). Interestingly, prostaglandin E2, a proinflammatory mediator, contributes to the progression of paratuberculosis infection by suppressing Th1 responses and activating IL-10 production (Sajiki et al., 2018).

In both sheep and cattle, IL-10 responses can also be elevated in early stages of disease (Nagata et al., 2010; de Silva et al., 2011) but does not appear to be related to disease susceptibility or resistance. The role of IL-10 varies and mathematical modelling indicates that it is related to infectious burden (Magombedze et al., 2015).

Further understanding of a role for IL-10 was gained through studies demonstrating that the addition of exogenous IL-10 to bovine cell cultures prior to infection with live MAP reduced IFN-γ secretion (Khalifeh and Stabel, 2004a). Alternatively, neutralization of IL-10 in johnin- PPD-stimulated whole blood increased IFN-γ production 23-fold in cattle with subclinical paratuberculosis (Buza et al., 2004). The effects of IL-10 on IFN-γ may be mediated through IL- 12, as the addition of exogenous IL-10 to human monocyte cultures reduces secretion of IL-12, whereas neutralization of IL-10 activity results in increased IL-12 secretion (Fulton et al., 1998).

Similarly, with bovine T cells, sensitization of a cow to mycobacteria with PPD and IL-12 resulted in an IL-12-mediated increase in IFN-γ secretion associated with decreased IL-10 expression (Tuo et al., 1999). Moreover, neutralization of IL-10 activity in bovine monocyte-derived macrophage cultures resulted in increased acidification of phagosomes, increased expression of IL-12, IL-8, TNF-α and MHC class II molecules, and increased killing of MAP in culture (Weiss et al., 2005). These studies provide evidence of the importance of interplay between Th1 and Th2 cytokines in the regulation of host responses to mycobacterial pathogens, allowing a balance to be maintained between protective and pathogenic responses.

Detailed analysis of T-cell responses at the ileal site of predilection in MAP infection is challenging. The development of a surgically isolated ileal loop model in newborn calves allowed study of localized immunity in the ileum during persistent MAP infection (Charavaryamath et al., 2013).

An accumulation of CD8+ T cells and γδ T cells in the lamina propria of infected intestinal segments was observed, concomitant with an increase in MAP-specific IFN-γ and TNF by leucocytes in the lamina propria. This is an interesting observation as a recently discovered subset of γδ T cells that co-expresses CD8γ+ is considered to play an important role in mucosal healing in inflammatory bowel disease (Kadivar et al., 2016). In addition, γδ T cells lose their responsiveness to MAP antigen in the clinical stages of disease (Albarrak et al., 2018). In ileal tissues of cattle with clinical disease, there is a significant increase in WC1+ γδ T cells expressing IL-10 and a significant increase in TGF-β expression by non-WC1+ cells compared with subclinical and non-infected cattle. However, there is no difference in expression of IFN-γ, IL-17 and TNF-α in mucosal cells, in these later stages of disease (Albarrak et al., 2018). In sheep, paucibacillary lesions are linked to a Th1/Th17 response, characterized by high levels of IL-12, IL-17A and IFN-γ, while multibacillary lesions are associated with a Th2 response and high levels of IL-5 and IL-10 (Burrells et al., 1998; Whittington et al., 2012). However, multibacillary lesions are unlikely to be solely driven by a Th2 response (Nicol et al., 2016). As disease progresses, Treg cells likely play an important role in controlling these changes (Robinson et al., 2011).

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Source: Behr Marcel A., Stevenson K., Kapur V. (eds.). Paratuberculosis: Organism, Disease, Control. 2nd edition. — CAB International,2020. — 439 p.. 2020

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