Helminth Infection and Commensal Microbiota Drive Early IL-10 Production in the Skin by CD4+ T Cells That Are Functionally Suppressive

Abstract

The skin provides an important first line of defence and immunological barrier to invasive pathogens, but immune responses must also be regulated to maintain barrier function and ensure tolerance of skin surface commensal organisms. In schistosomiasis-endemic regions, populations can experience repeated percutaneous exposure to schistosome larvae, however little is known about how repeated exposure to pathogens affects immune regulation in the skin. Here, using a murine model of repeated infection with Schistosoma mansoni larvae, we show that the skin infection site becomes rich in regulatory IL-10, whilst in its absence, inflammation, neutrophil recruitment, and local lymphocyte proliferation is increased. Whilst CD4+ T cells are the primary cellular source of regulatory IL-10, they expressed none of the markers conventionally associated with T regulatory (Treg) cells (i.e. FoxP3, Helios, Nrp1, CD223, or CD49b). Nevertheless, these IL-10+ CD4+ T cells in the skin from repeatedly infected mice are functionally suppressive as they reduced proliferation of responsive CD4+ T cells from the skin draining lymph node. Moreover, the skin of infected Rag-/- mice had impaired IL-10 production and increased neutrophil recruitment. Finally, we show that the mechanism behind IL-10 production by CD4+ T cells in the skin is due to a combination of an initial (day 1) response specific to skin commensal bacteria, and then over the following days schistosome-specific CD4+ T cell responses, which together contribute towards limiting inflammation and tissue damage following schistosome infection. We propose CD4+ T cells in the skin that do not express markers of conventional T regulatory cell populations have a significant role in immune regulation after repeated pathogen exposure and speculate that these cells may also help to maintain skin barrier function in the context of repeated percutaneous insult by other skin pathogens.

The peripheral immune response of mice infected with a neuropathogenic schistosome

“…On the other hand, CD4+GATA‐3+ (~Th2) proportion in the DLN for periphery and especially CD4+Foxp3+ (~Treg) cells in all observed lymphoid organs appeared to be increased suggesting they might contribute to IL‐10 production. As for Tregs, it is in contrast with their unchanged presence in the periphery DLN or spleen in early Schistosoma mansoni infection 28‐30 . Here, IL‐10 is produced by CD4+ T cells, 30 specifically Th2 28 or dermal dendritic cells 31 .…”

“…As for Tregs, it is in contrast with their unchanged presence in the periphery DLN or spleen in early Schistosoma mansoni infection 28‐30 . Here, IL‐10 is produced by CD4+ T cells, 30 specifically Th2 28 or dermal dendritic cells 31 . The regulatory milieu might be induced, among others, by skin commensal bacteria 30 .…”

“…Here, IL‐10 is produced by CD4+ T cells, 30 specifically Th2 28 or dermal dendritic cells 31 . The regulatory milieu might be induced, among others, by skin commensal bacteria 30 . The contribution of dendritic cells cannot be excluded in the case of T. regenti ‐infected mice as well because BMDCs prepared from mice 3 dpi significantly increased Il10 expression after exposure to rTrCB2.…”

CD4 T‐cell hyporesponsiveness induced by schistosome larvae is not dependent upon eosinophils but may involve connective tissue mast cells

“…So, it is perhaps surprising that we did not detect a significant reduction in IL‐10 cytokine production in the absence of eosinophils. However, we recently showed that in 4x schistosome‐infected mice, the majority of IL‐10 + cells in the skin were of lymphoid, rather than myeloid, origin . Thus, eosinophils are not a source of regulatory IL‐10 in our model despite their abundance.…”

Macrophages treated with antigen from the tapeworm Hymenolepis diminuta condition CD25 + T cells to suppress colitis

“…4), supporting the postulate that HdAg directly drove a unique, and putatively M reg phenotype. [The possibility that some gene changes were due to the trace levels of LPS contamination of the HdAg or the combined effect of helminth and microbe products cannot be excluded (52). ] Identification of the molecules in the HdAg that affects macrophage gene transcription and function ( i.e ., suppressed response to LPS) is important and will require extensive research efforts.…”