Intestinal helminth infection transforms the CD4+ T cell composition of the skin

Cajsa H Classon,Xiaogang Feng,Antonio Gigliotti Rothfuchs,Susanne Nylén,Emma Ringqvist,Liv Eidsmo,Louis Boon,Junjie Ma,Muzhen Li,Julian M Stark,Christopher A Tibbitt,Rebeca Cardoso,Jonathan M Coquet,Ada Lerma Clavero,Eduardo J Villablanca

doi:10.1038/s41385-021-00473-9

Abstract

Intestinal helminth parasites can alter immune responses to vaccines, other infections, allergens and autoantigens, implying effects on host immune responses in distal barrier tissues. We herein show that the skin of C57BL/6 mice infected with the strictly intestinal nematode Heligmosomoides polygyrus contain higher numbers of CD4+ T cells compared to the skin of uninfected controls. Accumulated CD4+ T cells were H. polygyrus-specific TH2 cells that skewed the skin CD4+ T cell composition towards a higher TH2/TH1 ratio which persisted after worm expulsion. Accumulation of TH2 cells in the skin was associated with increased expression of the skin-homing chemokine receptors CCR4 and CCR10 on CD4+ T cells in the blood and mesenteric lymph nodes draining the infected intestine and was abolished by FTY720 treatment during infection, indicating gut-to-skin trafficking of cells. Remarkably, skin TH2 accumulation was associated with impaired capacity to initiate IFN-γ recall responses and develop skin-resident memory cells to mycobacterial antigens, both during infection and months after deworming therapy. In conclusion, we show that infection by a strictly intestinal helminth has long-term effects on immune cell composition and local immune responses to unrelated antigens in the skin, revealing a novel process for T cell colonisation and worm-mediated immunosuppression in this organ.

Highlights

Immune responses in the gut and skin are deeply intertwined, as indicated by skin manifestations of intestinal disorders such as inflammatory bowel disease, Coeliac disease, small intestinal bacterial overgrowth and food allergies[1]
Intestinal H. polygyrus infection dampens skin recall responses We have previously shown that mice infected with H. polygyrus mount weaker delayed-type hypersensitivity (DTH) responses to BCG6,13
Intestinal worm infection impacts immune responses to other production induced after restimulation, revealing a strong H. polygyrus-specific TH2 component among the CD4+ T cells accumulating in the skin

Summary

Introduction

Immune responses in the gut and skin are deeply intertwined, as indicated by skin manifestations of intestinal disorders such as inflammatory bowel disease, Coeliac disease, small intestinal bacterial overgrowth and food allergies[1]. Intestinal worm infections have been suggested to have beneficial effects on inflammatory skin disorders with reduced atopy and allergic reactions in the skin[2,3]. We and others have shown that worm infection can dampen immune responses to infection and vaccination in the skin[4,5,6]. We recently described how a chronic intestinal infection with the model worm pathogen Heligmosomoides polygyrus bakerii causes redistribution of lymphocytes with the accumulation of T cells in the mesenteric lymph nodes (mesLNs)[6]. Worm-induced expansion of mesLNs resulted in atrophy and loss of T cells in skin-draining lymph nodes (LNs), leading to dampened responses in the skin to the tuberculosis vaccine Mycobacterium bovis Bacillus Calmette–Guérin (BCG)[6]

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Conclusion