Abstract
Efficient infection control requires potent T-cell responses at sites of pathogen replication. However, the regulation of T-cell effector function in situ remains poorly understood. Here, we show key differences in the regulation of effector activity between CD4+ and CD8+ T-cells during skin infection with HSV-1. IFN-γ-producing CD4+ T cells disseminated widely throughout the skin and draining lymph nodes (LN), clearly exceeding the epithelial distribution of infectious virus. By contrast, IFN-γ-producing CD8+ T cells were only found within the infected epidermal layer of the skin and associated hair follicles. Mechanistically, while various subsets of lymphoid- and skin-derived dendritic cells (DC) elicited IFN-γ production by CD4+ T cells, CD8+ T cells responded exclusively to infected epidermal cells directly presenting viral antigen. Notably, uninfected cross-presenting DCs from both skin and LNs failed to trigger IFN-γ production by CD8+ T-cells. Thus, we describe a previously unappreciated complexity in the regulation of CD4+ and CD8+ T-cell effector activity that is subset-specific, microanatomically distinct and involves largely non-overlapping types of antigen-presenting cells (APC).
Highlights
Infection results in the priming of pathogen-specific T-cell responses in lymph nodes (LN) draining the site of infection
herpes simplex virus (HSV)-1 is a widely distributed pathogen causing a life-long latent infection associated with periodic bouts of reactivation and severe clinical complications
Using a mouse model of HSV-1 skin infection, we describe a complex regulation of T-cell responses at the site of acute infection
Summary
Infection results in the priming of pathogen-specific T-cell responses in LNs draining the site of infection. While CD4+ helper T cells support the generation of antibody and CD8+ T-cell responses in lymphoid tissues, both CD4+ and CD8+ T-cells contribute directly to pathogen control at sites of infection [5,6] The latter is achieved through two principle effector functions: the contact-dependent elimination of infected tissue cells and the local production of inflammatory and antimicrobial cytokines [5,6]. Under circumstances where infection will result in lytic cell death regardless of T-cell killing, pathogen containment and clearance is dependent on the production of cytokines by effector CD4+ and CD8+ T cells [9,10,11] Together these diverse effector T-cell (TEFF) activities are essential for efficient immune protection, they may cause the destruction of uninfected tissues, as seen in the context of immunopathology, autoimmunity or transplant rejection. The cellular and molecular mechanisms controlling T-cell effector activities in nonlymphoid organs remain poorly defined [2,10]
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