Cutting Edge: Tissue-Retentive Lung Memory CD4 T Cells Mediate Optimal Protection to Respiratory Virus Infection

Abstract

We identify here a new class of lung tissue-resident memory CD4 T cells which exhibit tissue tropism and retention independent of antigen or inflammation. Tissue-resident memory CD4 T cells in the lung did not circulate or emigrate from the lung in parabiosis experiments, were protected from in vivo antibody labeling, and expressed elevated levels CD69 and CD11a compared to circulating memory populations. Importantly, influenza-specific lung-resident memory CD4 T cells served as in situ protectors to respiratory viral challenge, mediating enhanced viral clearance and survival to lethal influenza infection. By contrast, memory CD4 T cells isolated from spleen recirculated among multiple tissues without retention, and failed to mediate protection to influenza infection, despite their ability to expand and migrate to the lung. Our results reveal tissue compartmentalization as a major determining factor for immune-mediated protection in a key mucosal site, important for targeting local protective responses in vaccines and immunotherapies.

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

“…Trm cells can provide much more immediate protection, and various studies have demonstrated that they provide the most effective immune protection to the host 14, 15, 17, 30…”

“…Tissue resident memory cells are identified as CD69+ cells that remain within peripheral tissues following pathogen clearance 30, 31, 32. CD69 is thought to act as a retention signal as it inhibits the surface expression of the sphingosine‐1‐phosphate (S1P) receptor 1.…”

“…However, FTY720 may also inhibit egress of cells from peripheral tissues to draining lymph nodes and/or reduce cell survival 35, 41, 42, 43. Despite these potential caveats, results from FTY720‐treated animals reflect those from more elegant parabiosis experiments that demonstrate that Trm cells are a distinct population neither leaving the tissue nor being replenished by circulating cells 17, 30…”

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

“…The effector-memory (TEM) subset (Sallusto et al, 1999) is the predominant subset migrating through multiple tissues (Masopust et al, 2001); however, a significant fraction of TEM phenotype cells persist as non-circulating, tissue-resident subsets (TRM) in multiple sites including lungs, intestines, skin, liver, brain, and other mucosal surfaces (for reviews see (Mueller and Mackay, 2016;Schenkel and Masopust, 2014;Thome and Farber, 2015)). TRM mediate optimal protective responses to site-specific infections through rapid mobilization of immune responses in situ (Schenkel et al, 2014a;Teijaro et al, 2011). Mouse models have also demonstrated the feasibility of targeting TRM in vaccines for generating protective immunity (Shin and Iwasaki, 2012;Zens et al, 2016).…”

Skin TRM mediates distributed border patrol

“…More recently, another distinct subset, tissue-resident memory T cells (T RM ) have been described. T RM have been found in several tissues, including the skin, gut, lung and brain [3][4][5][6]. Once established, T RM are maintained independently of circulating T EM and T CM and their presence correlates with superior protection against local viral challenge [3,5,7].…”