Tuberculosis kills more than 1 million humans each year and is easily spread by aerosol infection. Importantly, after exposure to Mycobacterium tuberculosis (MTB) by inhalation, only a minority of contacts develops active pulmonary disease with mycobacterial replication and destruction of lung tissue. In the majority of exposed people, inhaled MTB is either killed by the innate immune system of the lung or triggers the development of granuloma structures around infected cells (Pai et al., 2016). The development of specific CD4+ T cell responses then induces control of mycobacterial growth without achieving eradication of MTB, a status referred to as latency (Pai et al., 2016). It is estimated that more than a quarter of the world’s population is latently infected with MTB. Their life-long risk to develop reactivation tuberculosis is around 5% and is influenced by a variety of genetic and environmental factors.

Parasitic helminth infections with intestinal nematodes, filaria, or trematodes affect an estimated number of >2 billion humans (Babu and Nutman, 2016). Similar to tuberculosis, helminth infections are often chronic and not acutely life-threatening. Epidemiologically, tuberculosis and helminth infections co-occur in many tropical and subtropical countries (Salgame et al., 2013). Immune responses to helminths in general are characterized by a strong Th2 component with production of IL-4, IL-5, IL-13, IL-10, and IgE (Babu and Nutman, 2016), whereas protective immunity to MTB requires robust Th1 immunity and is possibly enhanced by Th17 cells (Gopal et al., 2012; Monin et al., 2015). These diametrically opposed immunological biases and effector mechanisms raise the question how MTB and parasitic helminths mutually influence each other in co-infected individuals (Babu and Nutman, 2016). Interestingly, helminth infection of household contacts of patients with active, smear-positive tuberculosis increased the rate of tuberculin skin test conversion indicating a higher risk to become infected (Verhagen et al., 2012). Furthermore, active tuberculosis patients are more often co-infected with helminths than healthy counterparts (Elias et al., 2006; Tristão-Sá et al., 2002). Furthermore, helminth co-infection is associated with more advanced disease in tuberculosis patients and with reduced production of IFNγ but increased IL-10 (Resende Co et al., 2007). These findings indicate that the type 2 immune bias in helminth-infected individuals can impair the development of protective adaptive immunity to MTB. In contrast, other studies showed that underlying helminth infection can promote a Th2 and regulatory T cell response to MTB with a reduced risk to develop open, smear-positive pulmonary tuberculosis (Abate et al., 2015). In mice, infection with Nippostrongylus brasiliensis enhances bacterial load in the lung after MTB infection, an effect attributed to the action of alternatively activated macrophages (Potian et al., 2011).

Underlying helminth infection may also influence the response to vaccination with Mycobacterium bovis bacille Calmette-Guerin (BCG), which shows large geographic variation with reduced efficacy in countries with a high prevalence of worm infections (Roy et al., 2014; Colditz et al., 1994). Experimental infection of mice with Schistosoma (S.) mansoni or Heligmosomoides (H.) polygyrus impaired Th1 cell generation after vaccination with BCG (Elias et al., 2005; Obieglo et al., 2016), although another study found that chronic enteric infection with H. polygyrus did not interfere with primary or memory T cell responses to BCG (Rafi et al., 2015). Thus, these results from experimental mouse models show that not all helminth infections have a similarly strong impact on protective immunity to MTB. Anthelminthic treatment prior to BCG administration led to increased IFNγ and IL-12 production (Elias et al., 2001). It is noteworthy that maternal helminth infection during pregnancy negatively affected the frequency of IFNγ-producing T cells in cord blood of neonates (Gebreegziabiher et al., 2014) and the development of Th1 immunity in BCG-vaccinated offspring (Malhotra et al., 1999). However, attempts to enhance the immunogenicity of BCG vaccination by anthelminthic treatment of mothers during pregnancy were not successful (Webb et al., 2011).

Sensing of mycobacteria by the innate immune system is essential for a robust defense reaction, including the secretion of chemokines to attract leukocytes to the site of infection and the production of cytokines directing antigen-specific T cell responses toward Th1 and Th17 differentiation. Mycobacteria contain a plethora of PAMPs, for example, the TLR ligands 19 kDa lipoprotein, lipoarabinomannan (LAM), and mycobacterial DNA rich in CpG motifs (Mortaz et al., 2015). The hydrophobic cell wall of mycobacteria is especially rich in the glycolipid trehalose-6,6’-dimycolate (TDM, aka the cord factor), which is sufficient to trigger granulomatous reactions in vivo (Ishikawa et al., 2009), induces inflammatory cytokine production by macrophages (Geisel et al., 2005), and confers the Th1/Th17 adjuvant activity known from Freund’s complete adjuvant (Shenderov et al., 2013). TDM binds to the C-type lectin receptor (CLR) MINCLE (encoded by the Clec4e gene) (Ishikawa et al., 2009; Schoenen et al., 2010), which is inducibly expressed in macrophages (Matsumoto et al., 1999) and associates with the adapter protein Fc receptor gamma chain (FcRγ, encoded by Fcer1g) (Yamasaki et al., 2008). Signalling by MINCLE requires binding of the kinase SYK to the phosphorylated ITAM of the FcRγ, and proceeds via the CARD9-BCL10-MALT1 complex to activation of NFκB and expression of inflammatory target genes (Werninghaus et al., 2009; Ostrop and Lang, 2017). In addition to TDM, several additional glycolipids from the mycobacterial cell wall were recently identified as ligands for CLR, most of them like MINCLE members of the FcRγ-coupled DECTIN-2 family (Ishikawa et al., 2017). MCL, closely related to MINCLE and able to heterodimerize with it, also can bind TDM and in addition glycero-monomycolate (Furukawa et al., 2013; Miyake et al., 2013); DECTIN-2 binds mannose-capped LAM (Yonekawa et al., 2014) and DCAR is a receptor for mycobacterial phosphatidyl-inositol mannosides (Toyonaga et al., 2016). The prototypic myeloid signaling CLR, DECTIN-1 directly recruits SYK through its non-classical ITAM (Rogers et al., 2005) it, too, binds and is activated by an yet unidentified mycobacterial ligand (Rothfuchs et al., 2007). Since the signals emanating from the interaction of multiple CLR with MTB are transmitted through SYK-CARD9, it is not surprising that CARD9-deficient mice are highly susceptible to infection with MTB and succumb with high bacterial burden in the organs (Dorhoi et al., 2010). Knockout mice for individual CLR showed less severe phenotypes but were, dependent on the infection model employed, moderately more susceptible to infection (Wilson et al., 2015; Behler et al., 2015; Behler et al., 2012; Lee et al., 2012).

Already in the first report on MINCLE, the inducible expression in response to TLR stimulation with LPS and by the cytokine TNF was reported (Matsumoto et al., 1999). Indeed, TNF is essential for the upregulation of MINCLE in macrophages stimulated with the cord factor and for the Th17 promoting effect of the adjuvant CAF01 that contains the MINCLE ligand TDB (Schick et al., 2020). In contrast, the Th2 cytokines IL-4 and IL-13 downregulate expression of MINCLE, MCL, and DECTIN-2, in human monocytes/macrophages and DC, as well as in mouse bone marrow-derived macrophages (Hupfer et al., 2016; Ostrop et al., 2015). This inhibitory effect of the Th2 cytokines IL-4 and IL-13 depends on the transcription factor STAT6 and is associated with a reduced production of G-CSF and TNF by macrophages stimulated with the MINCLE ligand TDB, but not after stimulation with LPS (Hupfer et al., 2016). Thus, expression of the DECTIN-2 family CLR MINCLE, MCL, and DECTIN-2 is subject to a substantial regulation by the cytokines TNF and IL-4, which are key factors in type 1 and type 2 immune responses, respectively. Since type 2 immunity is a hallmark of many helminth infections, the question arises whether the expression and function of DECTIN-2 family CLR may be compromised during helminth infection in vivo (Lang and Schick, 2017).

Here, we have investigated the functional impact of IL-4 and helminth infection on myeloid responses to mycobacteria or the cord factor-based adjuvant TDB in vitro and in vivo. Our data show that IL-4 impairs MINCLE expression on monocytes in vivo, but does not interfere with phagocytosis of BCG. Underlying helminth infection attenuated immune responses to recombinant protein together with different adjuvants in the spleen but not in draining lymph nodes. The specific impairment of Th17 responses to MINCLE-dependent adjuvant indicates the contribution of downregulation of DECTIN-2 family CLR to vaccine antagonism induced by helminth infection.

In this study, we show for the first time that IL-4 impairs MINCLE expression and function in vivo. Two different models of helminth infection revealed an organ-specific impairment of Th17 induction by the MINCLE-dependent adjuvant CAF01 in the spleen. These findings establish an in vivo impact of IL-4 on the expression and function of MINCLE that may have important consequences for the detection of and the response to mycobacteria and their cell wall glycolipids in infection or vaccination.

In previous work, we have found that IL-4 downregulates expression of DECTIN-2 family CLRs in murine and human macrophages and DC (Hupfer et al., 2016). Here, we first extended these findings by showing that upregulation of these CLR by BCG was also impaired by IL-4 in BMM. Importantly, using overexpression of IL-4 in vivo by hydrodynamic injection of minicircle DNA, the upregulation of MINCLE on monocytes recruited after BCG infection to the peritoneum was strongly inhibited. This effect was cell type-specific, as it was not observed on recruited neutrophils, and it was also caused by infection with N. brasiliensis. We have previously shown that the downregulation of MINCLE in mouse macrophages by IL-4 requires the transcription factor STAT6 (Hupfer et al., 2016). It is at present unknown which other signalling pathways downstream or in parallel to STAT6 are involved in this process and how they may differ in monocytes/macrophages vs. neutrophils.

IL-4 and N. brasiliensis infection did not interfere with phagocytosis of BCG in vitro or in vivo, showing that high-level expression of DECTIN-2 family CLR is not required for phagocytosis of mycobacteria. This may seem surprising, as DECTIN-2 and MCL are phagocytic receptors (Sato et al., 2006; Arce et al., 2004), and mycobacteria strongly express ligands for both receptors (mannans and TDM). A lack of DECTIN-2 family CLR appears to be compensated by the large number of other receptors contributing to phagocytosis of mycobacteria, including the mannose receptor CD206, integrins like CD11b, or the inhibitory CLR DC-SIGN (Rajaram et al., 2017; Geijtenbeek et al., 2003; Melo et al., 2000).

Importantly, IL-4-treated macrophages not only downregulated DECTIN-2 family CLR, but in addition produced significantly less cytokines after stimulation with BCG. A similar reduction in G-CSF and TNF production was observed here in MINCLE- and FcRγ-deficient BMM. These observations suggests that IL-4 produced during helminth infection could interfere with the initial sensing of invading mycobacteria by pulmonary macrophages and thereby mute the generation of an inflammatory chemokine/cytokine as well as an anti-microbial response. If so, impaired detection of inhaled MTB by alveolar and lung macrophages may favour intracellular mycobacterial survival and replication, providing a mechanism underlying the reported increase in tuberculin skin test conversion reported for helminth-infected household contacts of patients with smear-positive tuberculosis (Verhagen et al., 2012). Whether IL-4 impairs functional macrophage responses to mycobacteria primarily through downregulation of MINCLE and DECTIN-2 family CLRs or by inhibiting other cytokine-inducing pathways is an open question that needs to be investigated in future work.

In addition to the response of macrophages to BCG, we investigated how type 2 immune bias during helminth infections impacts on the Th cell differentiation after recombinant subunit vaccination with MINCLE-dependent and -independent adjuvants. Induction of Th17 immunity triggered by the MINCLE-dependent adjuvant CAF01 was suppressed in two models of helminth infection in the spleen, but not in the draining popliteal and inguinal lymph nodes. This organ-specific impact of infection with N. brasiliensis and S. mansoni on splenic Th cell differentiation was associated with a stronger Th2 bias in the spleen, as demonstrated by the robustly increased levels of IL-4 and IL-10 released by splenocytes, but not draining lymph node cells, from worm-infected mice after polyclonal stimulation with anti-CD3 (Figures 4 and 5). Compartmentalized overexpression of IL-10 in the spleens but not lymph nodes has been described before in mice with chronic schistosomiasis (van der Vlugt et al., 2012). Our data suggest that such a restriction of Th2 bias to the spleen also applies to IL-4-producing T cells in both helminth infections. For infection with N. brasiliensis, we tested mice doubly deficient in Il4 and Il13 and confirmed a causal role of IL-4 and/or IL-13 in inhibition of both Th1 and Th17 differentiation in vivo after MINCLE-dependent immunization (Figure 6). Similar to the effect of IL-4 on macrophage cytokine responses, it remains to be dissected for the Th1/Th17 adjuvant effect whether the inhibitory effect of IL-4/IL-13 signals is partially or primarily caused by downregulation of DECTIN-2 family CLR in vivo.

Helminth infection did not alter the production of IL-17, IFNγ, or IL-10 by antigen-specific CD4+ T cells in the draining lymph nodes, as determined by re-stimulation of a defined number of cells with recombinant H1. However, the cellularity of the lymph nodes was significantly diminished by N. brasiliensis, suggesting that the total number of antigen-specific Th1/Th17 cells in the draining lymph nodes is reduced by co-existent worm infection. Decreased peripheral lymph node size and cellularity has been reported in mice infected with the enteric helminth H. polygyrus and was associated with a dampened immune response to infection with BCG, affecting primarily B and T lymphocytes (Feng et al., 2018). In the H. polygyrus model, the gut-draining mesenteric lymph nodes were increased in size, suggesting that atrophy of peripheral lymph nodes was due to a redistribution of lymphocytes (Feng et al., 2018). Furthermore, in mice infected with Helicobacter pylori, we have recently shown that concomitant schistosome infection lead to a redistribution of bacterial-specific CXCR3+ T cells resulting in reduced bacterial growth control (Bhattacharjee et al., 2019). Cell numbers and size of lymph nodes are controlled by entry of lymphocytes via the high endothelial venules and exit through the efferent lymphatics.

While the inhibition of IFNγ production by splenocytes from helminth-infected mice was impaired also after immunization with the TLR4 ligand G3D6A and the TLR9 ligand CpG ODN as adjuvants, IL-17 production was specifically impaired when the MINCLE-dependent CAF01 was the adjuvant. In addition, antigen-non-specific production of IFNγ by polyclonal anti-CD3 stimulation was also inhibited in splenocytes from helminth-infected mice, suggesting a general inhibitory effect of N. brasiliensis and S. mansoni infection that was not observed for production of IL-17. Thus, underlying helminth infection affects the CAF01-induced antigen-specific Th cell response in the spleen in a manner that could be explained by downregulation of MINCLE expression. Whether this is indeed the case needs to be further investigated in future studies comparing myeloid cells in spleen, peripheral lymph node, and subcutaneous injection site tissue. Detection and quantification of MINCLE surface protein on myeloid cells from tissues by flow cytometry is unfortunately complicated by the fact that proteolytic agents commonly used for enzymatic tissue dissociation cause a near-complete loss of specific staining (Stappers et al., 2021). For this reason, we employed here the intraperitoneal BCG infection model for assessment of IL-4/helminth effects on myeloid cells in vivo, because it allowed the direct flow cytometric staining of peritoneal exudate cells without the need for enzymatic tissue digestion.

Interestingly, application of schistosome eggs, a strong inducer of IL-4 and IL-13 production in vivo, prior to infection of mice with Salmonella typhimurium downregulated the Th17 response in the gut mucosa and impaired the clearance of the bacteria from the gut (Schramm et al., 2018). As the Salmonella cell wall contains trehalose phospholipids that bind to and activate MINCLE (Reinink et al., 2019), it is possible that induction of IL-17-producing cells during infection requires MINCLE and may be inhibited by schistosome eggs through IL-4/IL-13-induced downregulation of the receptor. Alternatively, IL-4 and IL-10 present in the spleen during helminth infection may act directly on antigen-specific Th cell differentiation after immunization and block Th17 (Park et al., 2005; Harrington et al., 2005) and Th1 bias (Paludan, 1998). Employment of conditional knockout mice with cell type-selective deficiency of the IL-4 receptor in myeloid or T cells in future experiments should be helpful to discriminate between these possibilities in our system of immunization in mice with concurrent helminth infection.

More generally, downregulation of other PRR in addition to DECTIN-2 family CLR during acute or chronic helminth infection may also have a negative impact on vaccines comprising specific PAMPs as adjuvants. Indeed, several papers have demonstrated a diminished baseline expression of TLR2 and TLR9 patients with filarial infection (Babu et al., 2009a; Babu et al., 2005). Underlying infection with hookworm or filaria were found to downregulate Th1 and Th17 responses in individuals with latent tuberculosis (Babu et al., 2009b; George et al., 2013). Certainly, helminth-induced immune regulation can interfere by diverse and manifold mechanisms with Th1/Th17 adaptive immunity. It will be worthwhile to investigate further, in animal models and in human patients with helminth infection, whether impaired DECTIN-2 family CLR expression is a significant contributor to thwarting of these protective anti-mycobacterial T cell responses.

For most figures, the data are directly shown as individual data points. These quantitative data are provided in the accompanying Excel files "Source data Schick et al.xls".

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Author details

1. Judith Schick

   Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

2. Meltem Altunay

   Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

   Contribution

   Formal analysis, Investigation, Visualization, Writing – review and editing

   Contributed equally with

   Matthew Lacorcia

   Competing interests

   No competing interests declared

3. Matthew Lacorcia

   1. Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Center for Global Health, Technische Universität München, Munich, Germany
   2. Center for Global Health, Technical University Munich, Munich, Germany

   Contribution

   Formal analysis, Investigation, Writing – review and editing

   Contributed equally with

   Meltem Altunay

   Competing interests

   No competing interests declared

4. Nathalie Marschner

   Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Stefanie Westermann

   Infektionsbiologische Abteilung, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

   Contribution

   Resources

   Competing interests

   No competing interests declared

6. Julia Schluckebier

   1. Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Center for Global Health, Technische Universität München, Munich, Germany
   2. Center for Global Health, Technical University Munich, Munich, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

7. Christoph Schubart

   Infektionsbiologische Abteilung, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

8. Barbara Bodendorfer

   Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

9. Dennis Christensen

   Adjuvant Research, Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark

   Contribution

   Resources, Writing – review and editing

   Competing interests

   No competing interests declared

10. Christian Alexander

    Cellular Microbiology, Forschungszentrum Borstel, Leibniz Lung Center Borstel, Borstel, Germany

    Contribution

    Resources

    Competing interests

    No competing interests declared

11. Stefan Wirtz

    Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

    Contribution

    Resources

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6936-7431

12. David Voehringer

    Infektionsbiologische Abteilung, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

    Contribution

    Formal analysis, Supervision, Funding acquisition, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6650-0639

13. Clarissa Prazeres da Costa

    1. Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Center for Global Health, Technische Universität München, Munich, Germany
    2. Center for Global Health, Technical University Munich, Munich, Germany

    Contribution

    Resources, Formal analysis, Supervision, Writing – review and editing

    Competing interests

    No competing interests declared

14. Roland Lang

    Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Visualization, Writing - original draft, Project administration, Writing – review and editing

    For correspondence

    roland.lang@uk-erlangen.de

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-0502-3677

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