Parasite-Specific CD4+ IFN-γ+ IL-10+ T Cells Distribute within Both Lymphoid and Nonlymphoid Compartments and Are Controlled Systemically by Interleukin-27 and ICOS during Blood-Stage Malaria Infection.

Ana Villegas-Mendez,Colette A Inkson,Tovah N Shaw,Kevin N Couper,J Brian De Souza,Patrick Strangward,J H Adams

doi:10.1128/iai.01100-15

Abstract

Immune-mediated pathology in interleukin-10 (IL-10)-deficient mice during blood-stage malaria infection typically manifests in nonlymphoid organs, such as the liver and lung. Thus, it is critical to define the cellular sources of IL-10 in these sensitive nonlymphoid compartments during infection. Moreover, it is important to determine if IL-10 production is controlled through conserved or disparate molecular programs in distinct anatomical locations during malaria infection, as this may enable spatiotemporal tuning of the regulatory immune response. In this study, using dual gamma interferon (IFN-γ)–yellow fluorescent protein (YFP) and IL-10–green fluorescent protein (GFP) reporter mice, we show that CD4+ YFP+ T cells are the major source of IL-10 in both lymphoid and nonlymphoid compartments throughout the course of blood-stage Plasmodium yoelii infection. Mature splenic CD4+ YFP+ GFP+ T cells, which preferentially expressed high levels of CCR5, were capable of migrating to and seeding the nonlymphoid tissues, indicating that the systemically distributed host-protective cells have a common developmental history. Despite exhibiting comparable phenotypes, CD4+ YFP+ GFP+ T cells from the liver and lung produced significantly larger quantities of IL-10 than their splenic counterparts, showing that the CD4+ YFP+ GFP+ T cells exert graded functions in distinct tissue locations during infection. Unexpectedly, given the unique environmental conditions within discrete nonlymphoid and lymphoid organs, we show that IL-10 production by CD4+ YFP+ T cells is controlled systemically during malaria infection through IL-27 receptor signaling that is supported after CD4+ T cell priming by ICOS signaling. The results in this study substantially improve our understanding of the systemic IL-10 response to malaria infection, particularly within sensitive nonlymphoid organs.

Highlights

The control and resolution of blood-stage malaria infection are mediated through dynamic and bidirectional interactions between effector and regulatory components of the immune system
We show using dual gamma interferon (IFN-␥)–yellow fluorescent protein (YFP) and IL-10 – green fluorescent protein (GFP) reporter mice that antigen-experienced CD4ϩ IFN-␥ϩ T cells are the dominant source of IL-10 in both lymphoid and nonlymphoid compartments during the course of P. yoelii infection
We have shown, using novel IFN-␥–YFP and IL-10 – GFP dual-reporter mice, that antigen-experienced and not homeostatic or bystander-activated effector CD4ϩ IFN-␥ϩ T cells are the dominant source of IL-10 in both lymphoid and nonlymphoid compartments throughout the course of malaria infection

Summary

Introduction

The control and resolution of blood-stage malaria infection are mediated through dynamic and bidirectional interactions between effector and regulatory components of the immune system. Immune-mediated pathology typically manifests in nonlymphoid organs, such as the liver, lung, and brain, in IL-10-deficient mice during malaria infection [5, 7, 21]. This suggests that IL-10 plays a key regulatory role within these tissue sites in regulating tissue-damaging inflammation during infection. CD4ϩ T cells appear to be the predominant source of IL-10 in the spleen in mice [5, 22, 23] and blood in humans [24, 25], during blood-stage malaria infection, IL-10 can be produced by virtually all leukocyte populations [19]. A myriad of context-dependent pathways can instruct and/or stabilize IL-10 expression by CD4ϩ T cell subsets [1, 29]

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Results

Conclusion