Mycobacterium avium Subspecies paratuberculosis Drives an Innate Th17-Like T Cell Response Regardless of the Presence of Antigen-Presenting Cells

Abstract

The gastrointestinal disease of ruminants is clinically known as Johne's disease (JD) and is caused by Mycobacterium avium subspecies paratuberculosis (MAP). An accumulative effect by insensitive diagnostic tools, a long subclinical stage of infection, and lack of effective vaccines have made the control of JD difficult. Currently lacking in the model systems of JD are undefined correlates of protection and the sources of inflammation due to JD. As an alternative to commonly studied immune responses, such as the Th1/Th2 paradigm, a non-classical Th17 immune response to MAP has been suggested. Indeed MAP antigens induce mRNAs encoding the Th17-associated cytokines IL-17A, IL-17F, IL-22, IL-23, IL-27, and IFNγ in CD3+ T cell cultures as determined by RT-qPCR. Although not as robust as when cultured with monocyte-derived macrophages (MDMs), MAP is able to stimulate the upregulation of these cytokines from sorted CD3+ T cells in the absence of antigen-presenting cells (APCs). CD4+ and CD8+ T cells are the main contributors of IL-17A and IL-22 in the absence of APCs. However, MAP-stimulated MDMs are the main contributor of IL-23. In vivo, JD+ cows have more circulating IL-23 than JD-cows, suggesting that this proinflammatory cytokine may be important in the etiology of JD. Our data in this study continue to suggest that Th17-like cells and associated cytokines may indeed play an important role in the immune responses to MAP infection and the development or control of JD.

Revealing immune responses in the Mycobacterium avium subsp. paratuberculosis-infected THP-1 cells using single cell RNA-sequencing

“…Moreover, the immune regulatory role of IL-10 has been considered to contribute to the persistence of MAP in the host immune system. Recently, the Th17-like response has been thought to be a major response to MAP infection associated with granuloma formation [33][34][35]. Early expression of Th17-induced cytokines such as IL-17a is associated with activation of innate T lymphocytes induced by IL-1β, IL-6, and IL-23 produced by phagocytic cells [9].…”

Mycobacterium avium subsp. paratuberculosis antigens induce cellular immune responses in cattle without causing reactivity to tuberculin in the tuberculosis skin test

“…While IFN-g has long been considered as a hallmark cytokine in providing protection against mycobacterial intracellular pathogens (45), its role as a sole cytokine in providing protection against mycobacterial pathogens has been challenged (46,47). Recent evidence indicates that Th17mediated immune responses also contribute to the early inflammatory responses to mycobacterial infection, thus potentially play a crucial role in providing protective immunity against M. tuberculosis and MAP (46,(48)(49)(50). The current results demonstrated that antigen-specific IL-17A levels (both at the protein and mRNA levels) were significantly upregulated in animals vaccinated with the rMAP fusion protein.…”

Genome-wide association analysis for susceptibility to infection by Mycobacterium avium ssp. paratuberculosis in US Holsteins

“…Likewise, increased IL-17 has been observed in plasma from cows that are both ELISA and fecal test-positive for antibodies to MAP (Dudemaine et al, 2014). Also, treatment of bovine peripheral blood mononuclear cells with MAP antigens has resulted in increased secretion of IL-17A (DeKuiper and Coussens, 2019), and MAP antigens induce increased expression of IL17A mRNA in cultured bovine T-cells (DeKuiper et al, 2020).…”