Abstract
The balance of type 1 and type 2 immune responses plays a crucial role in anti-helminth immunity and can either support chronic infection or drive type 2 mediated expulsion of the parasite. Helminth antigens and secreted molecules directly influence this balance and induce a favorable immunological environment for the parasite’s survival. However, less is known if the site of infection also influences the balance of type 1 and type 2 immunity. Here, we report that tissue-specific immune responses are mounted against helminth antigens, which elicited strong IL-4 responses when injected into the skin, while the same antigen, delivered into the intestinal subserosa, induced increased IFN-γ and reduced Th2 responses. Immune responses in individual mesenteric lymph nodes that drain defined regions of the intestine furthermore displayed a site-specific pattern of type 1 and type 2 immunity after Schistosoma mansoni or Heligmosomoides polygyrus infection. S. mansoni egg-specific Th2 responses were detectable in all mesenteric lymph nodes but Th1 responses were only present in those draining the colon, while H. polygyrus infection elicited mixed Th1 and Th2 responses in the lymph nodes associated with the site of infection. Similar site-specific type 1 and type 2 immune responses were observed in the draining lymph nodes after the controlled delivery of S. mansoni eggs into different segments of the small and large intestine using microsurgical techniques. Different subsets of intestinal dendritic cells were hereby responsible for the uptake and priming of Th1 and Th2 responses against helminth antigens. Migratory CD11b+CD103− and especially CD11b+CD103+ DC2s transported S. mansoni egg antigens to the draining lymph nodes to induce Th1 and Th2 responses, while CD103+ DC1s induced only IFN-γ responses. In contrast, H. polygyrus antigens were predominantly transported by CD11b+CD103− DC2s and CD103+ DC1s and all DC subsets induced similar Th1 but weaker Th2 responses, compared to S. mansoni egg antigens. The development of adaptive anti-helminth immune responses is therefore influenced by the antigen itself, the uptake and priming characteristics of antigen-positive dendritic cell subsets and the site of infection, which shape the level of Th1 and Th2 responses in order to create a favorable immunological environment for the parasite.
Highlights
The balance of different types of immune responses plays an important role in orchestrating the optimal immunological environment to appropriately counter infections
This effect is perhaps best demonstrated during the infection of the nematode Trichuris muris where Interleukin-4 (IL-4) and IL13 mediated Th2 responses lead to rapid expulsion in resistant mouse strains, whereas susceptible mouse strains produce high levels of Interferon-gamma (IFN-g), IL-12 and IL-18, which are characteristic of a predominant Th1 response [5, 6]
In the popliteal lymph nodes approximately 2% of PMA/ionomycin stimulated CD4+ T cells produced IFN-g after egg injection into the footpad, whereas up to 4% of CD4+ T cells in the mesenteric lymph nodes (MLNs) were IFN-g+ after subserosal egg injection (Figures 1A, B; Supplementary Figure 1A)
Summary
The balance of different types of immune responses plays an important role in orchestrating the optimal immunological environment to appropriately counter infections. The analysis of RORgt+ Th17 and Foxp3+ T regulatory cell development after controlled antigen delivery into different segments of the intestine revealed that tolerogenic responses preferentially develop in LNs draining the proximal intestine while Th17 responses are more pronounced in the LNs draining the distal intestine [30] This observation demonstrated that effector T cell differentiation can directly be influenced by location-specific factors, suggesting that the distinct phenotypes and proportions of pro-inflammatory and T regulatory cells, reported in numerous tissues and LNs [31,32,33], might be maintained and initiated by location-specific cues. Different helminth antigens were taken up by distinct subsets of intestinal migratory dendritic cells, which induced distinct levels of Th1 and Th2 responses, indicating that lymph node-specific type 1 and type 2 immune responses against helminth antigens are modulated by the antigen itself, antigen-positive dendritic cells and the site of infection
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