CC Chemokine Receptor 7 Expression by Effector/Memory CD4⁺T Cells Depends on Antigen Specificity and Tissue Localization during Influenza A Virus Infection

Abstract

The lung is an important entry site for respiratory pathogens such as influenza A virus. In order to combat such invading infectious agents, effector/memory T cells home to the lung and other peripheral tissues as well as lymphoid organs. In this process, chemokines and their receptors fulfill important roles in the guidance of T cells into such organs and specialized microenvironments within tissues. In this study, we determined if CD4 ؉ T cells residing in different lung compartments and draining lymph nodes of influenza A virus-infected and naïve mice express receptors allowing their recirculation into secondary lymphoid tissues. We found high levels of L-selectin and CC chemokine receptor 7 (CCR7) expression in lung-derived CD4 ؉ T cells, similar to that detected on T cells in secondary lymphoid organs. Upon influenza A virus infection, the bulk of gamma interferon-positive (IFN-␥ ؉ ) and IFN-␥ ؊ CD4 ؉ T cells recovered from lung parenchyma retained functional CCR7, whereas virus-specific IFN-␥-producing T cells were CCR7؊ . In contrast, a majority of virus-specific IFN-␥ ؉ T cells in the lung draining lymph node were CCR7 ؉ . Independent of infection, CD4 ؉ T cells obtained from the lung airways exhibited the lowest expression level of L-selectin and CCR7, indicating that T cells at this anatomical site represent the most differentiated effector cell type, lacking the ability to recirculate. Our results suggest that effector/memory T cells that enter inflammatory sites retain functional CCR7 expression, which is lost only upon response to viral antigen and after localization to the final effector site.

CCR7 Deficiency Leads to Leukocyte Activation and Increased Clearance in Response to Pulmonary Pseudomonas aeruginosa Infection

“…CCL19 and CCL21 expression has been identified in peripheral organs, such as the lung (27,43), but their role in host defense is not fully understood. Previous studies employing models of pulmonary infection have shown that CCR7 deficiency leads to impaired host defense (1,6,15,18,19,22,31). However, we demonstrated that CCR7 deficiency FIG.…”

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

“…We have previously shown in a lung inflammation model that only effector T cells isolated from the tissue (or bronchoalveolar lavage fluid) have down-regulated CCR7 [43], suggesting a model of differentiation of both inflammatory as well as suppressor T cells from naive to antigenexperienced -but still recirculating -effector/memory cells to a final stage possessing the capacity to enter, but not to exit, the peripheral target tissue. We here provide evidence that forced accumulation due to CCR7 deficiency results in a significant increase in suppressive activity, confirming that Treg tissue exit via CCR7 contributes to the functional regulation of inflammatory responses.…”

Tissue Exit: a Novel Control Point in the Accumulation of Antigen-Specific CD8 T Cells in the Influenza A Virus-Infected Lung

“…In further support that antigen recognition by T cells in tissues leads to downregulation of CCR7 expression or function, previous studies show that while most infiltrating CD4 T cells are responsive to CCL21 (15), influenza virus-specific CD4 T cells in the infected lung are CCR7 Ϫ (15,47). In addition, Arnold and colleagues demonstrated that naïve CD4 T cells transiently reduce responsiveness to CCR7 ligands following antigen recognition in lymph nodes (2).…”

“…CD8 (clone 53-6.7), CD4 (clone RM4-5), and Thy1.1 (clone HIS51) rat anti-mouse monoclonal antibodies (eBioscience) were used to recognize surface markers. Binding of mouse CCL19 fused to human IgG (eBioscience) was used to stain for CCR7 as described previously (15). Human immunoglobulin G was used as a control.…”