Editors' ChoiceIMMUNITY

The lung’s defensive line

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Science Translational Medicine  16 Nov 2016:
Vol. 8, Issue 365, pp. 365ec184
DOI: 10.1126/scitranslmed.aal0072

In a contest between the human body and bugs, a phenomenon called tissue resident memory provides a blitz-defense, rushing the bugs to block repeat infection. Tissue-resident memory T cells—a lymphocyte lineage that resides in tissues rather than reentering the circulation—protect against pathogens by virtue of their anatomical restriction at sites with a high probability of reinfection, such as the lung. This long-term retention and ability to rapidly respond to intruders indicates that memory T cells must also acquire specialized functions that balance potent antipathogen activity with limited tissue destruction. In a new study, Hombrink et al. present a transcriptional analysis revealing programs that distinguish circulating from resident memory in humans.

To study lung-resident memory CD8+ T cells in humans, the authors isolated CD45RACD8+ T cells from paired samples of healthy lung and peripheral blood. Global gene expression profiles were collected both before and after ex vivo stimulation of the T cell receptor. Unstimulated memory cells clustered by anatomical site, indicating common programs specific to tissue site of isolation. Direct comparison of lung resident and circulating effector memory T cells revealed a signature suggestive of resident cells’ specialized function. Tissue resident T cells exhibited enhanced expression of chemokines and adhesion molecules required for retention in epithelial layers and down-regulated receptors necessary for homing to the lymphatic system and transmigration through endothelium lining the blood vessels. Unstimulated resident memory cells expressed constitutive levels of effector transcripts equal to that of stimulated circulating memory cells, indicating potential for rapid protein translation. Although poised for rapid response, significant expression of inhibitory molecules suggested restraint, perhaps to ensure limited tissue damage caused by inflammation associated with the adaptive immune response. Maintenance of tissue resident memory cells in mouse lung was dependent on Notch proteins, which are involved in cell differentiation decisions. Lung epithelial cells and CD11b+ lung dendritic cells express Notch ligands, which, when added to ex vivo cultures of isolated resident memory T cells, helped to maintain high expression of IFNγ, a cytokine required for T cell function. Furthermore, deletion of Notch1 and Notch2 from T cells in mice prevented the accumulation of resident memory cells after influenza A infection. Short-term inhibition of Notch by a γ-secretase inhibitor decreased expression of CD103, which is required for epithelial localization of resident memory T cells; this led to a reduction in the numbers of pre-established anti-influenza A resident memory T cells. Elucidation of the specialized biology of human tissue resident memory T cells may generate design principles for vaccination strategies that take advantage of this potent source of immune protection at tissue barriers.

P. Hombrink et al., Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells. Nat. Immunol. 10.1038/ni.3589 (2016). [Abstract]

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