Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy

Abstract

Influenza-induced lung edema and inflammation are exacerbated by a positive feedback loop of cytokine and chemokine production termed a ‘cytokine storm’, a hallmark of increased influenza-related morbidity and mortality. Upon infection, an immune response is rapidly initiated in the lungs and draining lymph node, leading to expansion of virus-specific effector cells. Using two-photon microscopy, we imaged the dynamics of dendritic cells (DC) and virus-specific eGFP+CD8+ T cells in the lungs and draining mediastinal lymph nodes during the first two weeks following influenza infection. Three distinct phases of T cell and CD11c+ DC behavior were revealed: 1) Priming, facilitated by the arrival of lung DCs in the lymph node and characterized by antigen recognition and expansion of antigen-specific CD8+ T cells; asymmetric T cell division in contact with DCs was frequently observed. 2) Clearance, during which DCs re-populate the lung and T cells leave the draining lymph node and re-enter the lung tissue where enlarged, motile T cells come into contact with DCs and form long-lived interactions. 3) Maintenance, characterized by T-cell scanning of the lung tissue and dissociation from local antigen presenting cells; the T cells spend less time in association with DCs and migrate rapidly on collagen. A single dose of a sphingosine-1-phosphate receptor agonist, AAL-R, sufficient to suppress influenza-induced cytokine-storm, altered T cell and DC behavior during influenza clearance, delaying T cell division, cellular infiltration in the lung, and suppressing T-DC interactions in the lung. Our results provide a detailed description of T cell and DC choreography and dynamics in the lymph node and the lung during influenza infection. In addition, we suggest that phase lags in T cell and DC dynamics induced by targeting S1P receptors in vivo may attenuate the intensity of the immune response and can be manipulated for therapeutic benefit.

Tissue Distribution of Memory T and B Cells in Rhesus Monkeys following Influenza A Infection

“…These finding may not be surprising because priming of naive T cells by dendritic APCs occurs in the mediastinal lymph nodes (38,39). Preferential localization of memory T cells to the lungs occurred during the contraction phase, 49-58 d after second virus inoculation.…”

Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation

“…Bulge-associated Tregs displayed a more amoeboid cell morphology with increased protrusive activity (Figures 3E and movies S1 and S2). This differential cell shape was quantified in individual skin Tregs by applying a measure of relative sphericity (Matheu et al, 2013; Zaid et al, 2014). Cells that are in contact with other cells typically have characteristic dynamic behavior.…”

Location, Location, Location: The Impact of Migratory Heterogeneity on T Cell Function

“…T-bet induction is accompanied by the expression of CXCR3 (34) that binds the chemokines CXCL9, CXCL10, and CXCL11, which are frequently associated with inflammation. Asymmetric division can be associated with differential partitioning of T-bet (35, 36) and might also contribute to effector cell heterogeneity. This concept has been predominantly studied in terms of the generation of effector T cells that give rise to subsets memory cells that differentially express CD62L/CCR7 (see Role of Location and MR Signaling on the Effector to Memory T Cell Transition).…”