ICOS controls Foxp3+ regulatory T‐cell expansion, maintenance and IL‐10 production during helminth infection

Stephen A Redpath,Nienke Van Der Werf,Andrew S Macdonald,Rick M Maizels,David Gray,Matthew D Taylor,Ana M Cervera

doi:10.1002/eji.201242794

Abstract

Foxp3+ regulatory T (Treg) cells are key immune regulators during helminth infections, and identifying the mechanisms governing their induction is of principal importance for the design of treatments for helminth infections, allergies and autoimmunity. Little is yet known regarding the co-stimulatory environment that favours the development of Foxp3+ Treg-cell responses during helminth infections. As recent evidence implicates the co-stimulatory receptor ICOS in defining Foxp3+ Treg-cell functions, we investigated the role of ICOS in helminth-induced Foxp3+ Treg-cell responses. Infection of ICOS−/− mice with Heligmosomoides polygyrus or Schistosoma mansoni led to a reduced expansion and maintenance of Foxp3+ Treg cells. Moreover, during H. polygyrus infection, ICOS deficiency resulted in increased Foxp3+ Treg-cell apoptosis, a Foxp3+ Treg-cell specific impairment in IL-10 production, and a failure to mount putatively adaptive Helios−Foxp3+ Treg-cell responses within the intestinal lamina propria. Impaired lamina propria Foxp3+ Treg-cell responses were associated with increased production of IL-4 and IL-13 by CD4+ T cells, demonstrating that ICOS dominantly downregulates Type 2 responses at the infection site, sharply contrasting with its Type 2-promoting effects within lymphoid tissue. Thus, ICOS regulates Type 2 immunity in a tissue-specific manner, and plays a key role in driving Foxp3+ Treg-cell expansion and function during helminth infections.

Highlights

Helminth parasites excel at subverting the host’s immune regulatory pathways resulting in immunosuppressed hosts harbouring www.eji-journal.eu chronic infections [1, 2]
Immune downregulation plays a beneficial role in protecting the host from pathology during chronic infection, and helminth infections are linked to the amelioration of allergy and autoimmune diseases indicating that helminth-induced immune suppression can be therapeutically applied to the treatment of these conditions [3, 4]
As ICOS is involved in a range of T-cell responses, we hypothesised that ICOS co-stimulation represents a common pathway by which Foxp3+ Treg-cell responses are promoted to distinct helminths

Summary

Introduction

Helminth parasites excel at subverting the host’s immune regulatory pathways resulting in immunosuppressed hosts harbouring www.eji-journal.eu chronic infections [1, 2]. This immune suppression forms a major barrier to the acquisition of protective Th2 immunity, both in regard to natural infections and potential vaccination. Immune downregulation plays a beneficial role in protecting the host from pathology during chronic infection, and helminth infections are linked to the amelioration of allergy and autoimmune diseases indicating that helminth-induced immune suppression can be therapeutically applied to the treatment of these conditions [3, 4]. Foxp3+ Treg cells are a fundamental mechanism of immune regulation during helminth infections, and an understanding of the mechanisms governing the induction of Foxp3+ Treg-cell responses is of principal importance for the design of both prophylactic helminth treatments and therapies for allergies and autoimmunity

Methods

Results

Conclusion