Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells

Denton, A.E., Roberts, E.W. , Linterman, M.A. and Fearon, D.T. (2014) Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells. Proceedings of the National Academy of Sciences of the United States of America, 111(33), pp. 12139-12144. (doi: 10.1073/pnas.1412910111) (PMID:25092322) (PMCID:PMC4143042)

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Abstract

Fibroblastic reticular cells (FRCs), through their expression of CC chemokine ligand (CCL)19 and CCL21, attract and retain T cells in lymph nodes (LNs), but whether this function applies to both resting and activated T cells has not been examined. Here we describe a model for conditionally depleting FRCs from LNs based on their expression of the diphtheria toxin receptor (DTR) directed by the gene encoding fibroblast activation protein-α (FAP). As expected, depleting FAP+ FRCs causes the loss of naïve T cells, B cells, and dendritic cells from LNs, and this loss decreases the magnitude of the B- and T-cell responses to a subsequent infection with influenza A virus. In contrast, depleting FAP+ FRCs during an ongoing influenza infection does not diminish the number or continued response of activated T and B cells in the draining LNs, despite still resulting in the loss of naïve T cells. Therefore, different rules govern the LN trafficking of resting and activated T cells; once a T cell is engaged in antigen-specific clonal expansion, its retention no longer depends on FRCs or their chemokines, CCL19 and CCL21. Our findings suggest that activated T cells remain in the LN because they down-regulate the expression of the sphingosine-1 phosphate receptor-1, which mediates the exit of lymphocytes from secondary lymphoid organs. Therefore, LN retention of naïve lymphocytes and the initiation of an immune response depend on FRCs, but is an FRC independent and possibly cell-autonomous response of activated T cells, which allows the magnitude of clonal expansion to determine LN egress.

Item Type:Articles
Additional Information:The work was supported by the Ludwig Institute for Cancer Research, the Wellcome Trust, and Cancer Research UK. M.A.L. was supported by an Australian National Health and Medical Research Council Overseas Biomedical Fellowship and E.W.R. was supported by the Wellcome Trust PhD Programme.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Roberts, Dr Ed
Authors: Denton, A.E., Roberts, E.W., Linterman, M.A., and Fearon, D.T.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:04 August 2014

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