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Cutting Edge: Contribution of Lung-Resident T Cell Proliferation to the Overall Magnitude of the Antigen-Specific CD8 T Cell Response in the Lungs following Murine Influenza Virus Infection

Department of Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
The Journal of Immunology (Impact Factor: 5.36). 10/2009; 183(7):4177-81. DOI: 10.4049/jimmunol.0901109
Source: PubMed

ABSTRACT Following influenza virus infection, CD8 T cells encounter mature, Ag-bearing dendritic cells within the draining lymph nodes and undergo activation, programmed proliferation, and differentiation to effector cells before migrating to the lungs to mediate viral clearance. However, it remains unclear whether CD8 T cells continue their proliferation after arriving in the lungs. To address this question, we developed a novel, in vivo, dual-label system using intranasal CFSE and BrdU administration to identify virus-specific CD8 T cells that are actively undergoing cell division while in the lungs. With this technique we demonstrate that a high frequency of virus-specific CD8 T cells incorporate BrdU while in the lungs and that this lung-resident proliferation contributes significantly to the magnitude of the Ag-specific CD8 T cell response following influenza virus infection.

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    • "Even after leaving the central lymphoid organs and trafficking via the blood to the peripheral site of infection, CD8 + effector CTL continue to engage in antigen-specific interactions that (apart from resulting in cytolysis of infected targets) drive further proliferation and cytokine release. A combination of local CFSE and BrdU administration reveals extensive continued proliferation of newly arrived CTL in the lung contributing substantially to the overall magnitude of the response to influenza infection (Bedoui and Gebhardt, 2011; McGill and Legge, 2009). The greatest on-site proliferation coincides with the appearance in the lung on monocyte-derived inflammatory DCs. "
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    ABSTRACT: Resting naive CD8(+) T cells have an astounding capacity to react to pathogens by massive expansion and differentiation into cytotoxic effector cells that migrate to all corners of the body to clear the infection. The initial interaction with antigen-presenting cells in the central lymphoid organs drives an orchestrated program of differentiation aimed at producing sufficient numbers of effectors to get the job done without resulting in clonal exhaustion. Interactions with antigen-presenting cells and other immune cells continue at the site of infection to regulate further on-site expansion and differentiation, all with the goal of protecting the host with minimal bystander tissue damage. Here we review recent advances in CD8(+) T cell recognition of antigen in lymphoid as well as in nonlymphoid tissues in the periphery, and how CD8(+) T cell expansion and differentiation are controlled in these contexts.
    Immunity 08/2011; 35(2):161-8. DOI:10.1016/j.immuni.2011.07.010 · 19.75 Impact Factor
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    • "Once in the lung, effector CD8 + T cells are subjected to a highly inflammatory environment, and can reencounter antigen presented by local dendritic cells, infected epithelial cells, and other cells. These interactions can drive additional T cell proliferation and differentiation, which contribute to the magnitude of the effector T cell response (McGill and Legge, 2009). In addition, the interaction of effector CD8 + T cells and dendritic cells in the lung promotes T cell survival via IL-15 transpresentation (McGill et al., 2010). "
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    ABSTRACT: The airway luminal memory CD8 T cells induced by respiratory mucosal immunization in a murine model have been found to be critical to antituberculosis immunity. However, the mechanisms of their maintenance on airway mucosal surface still remain poorly understood. Using a model of adenovirus-based intranasal immunization we investigated the immune property and the mechanisms of maintenance of airway luminal CD8 T cells. Immune properties of airway luminal Mycobacterium tuberculosis antigen-specific CD8 T cells were examined. Proliferation of airway luminal CD8 T cells was determined by in vivo T cell-labeling techniques. The role of peripheral T cell recruitment in maintaining airway luminal CD8 T cells was investigated by blocking lymphocyte trafficking from lymphoid and peripheral tissues. The requirement of M. tuberculosis antigens for in situ T cell proliferation was evaluated using a T cell transfer approach. An airway M. tuberculosis challenge model was used to study the relationship between CD8 T cell-mediated protection and peripheral T cell recruitment. Intranasal immunization leads to elicitation of persisting M. tuberculosis antigen-specific CD8 T cells in the airway lumen, which display an activated effector memory phenotype different from those in peripheral tissues. Airway luminal T cells continuously proliferate in an antigen-dependent manner, and can be maintained even in the absence of peripheral T cell recruitment. The lungs equipped with such CD8 T cells are protected from airway M. tuberculosis challenge independent of both peripheral T cell supply and CD4 T cells. Vaccine-inducible airway luminal antituberculosis memory CD8 T cells are self-renewable in an antigen-dependent manner, and can be maintained independent of peripheral T cell supply.
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