CD49a Identifies Polyfunctional Memory CD8 T cell Subsets that Persist in the Lungs after Influenza Infection

Abstract

CD8 T cell memory offers critical antiviral protection, even in the absence of neutralizing antibodies. The paradigm is that CD8 T cell memory within the lung tissue consists of a mix of circulating TEM cells and non-circulating TRM cells. However, based on our analysis, the heterogeneity within the tissue is much higher, identifying TCM, TEM, TRM, and a multitude of populations which do not perfectly fit these classifications. Further interrogation of the populations shows that TRM cells that express CD49a, both with and without CD103, have increased and diverse effector potential compared with CD49a negative populations. These populations function as a one-man band, displaying antiviral activity, chemokine production, release of GM-CSF, and the ability to kill specific targets in vitro with delayed kinetics compared with effector CD8 T cells. Together, this study establishes that CD49a defines multiple polyfunctional CD8 memory subsets after clearance of influenza infection, which act to eliminate virus in the absence of direct killing, recruit and mature innate immune cells, and destroy infected cells if the virus persists.

Maintenance of the virus-specific CD8+ T-cell repertoire: Implications for vaccine strategies

“…Several studies have shown that TRM cells are potent cytokine producers [342][343][344]. Expression of CD49a has been linked to enhanced cytokine production of TRM cells in the skin [354] and to a polyfunctional phenotype of lung TRM cells [355]. Our findings that antigen-specific T cells expressing CD49a, CD69 or CD103 in the lung are associated with IFNγ-production supports these previous reports.…”

“…Lung TRM cells cannot be solely identified by expression of (a combination of) CD49a, CD69 and CD103, as some TRM cells have been described to be negative for these markers [355,356]. To distinguish between lung TRM cells and circulating T cells, an intravenous (i.v.)…”

Mouse Memory CD8 T cell subsets defined by Tissue Resident Memory (TRM) Integrin Expression Exhibit Distinct Metabolic Profiles

“…These findings all correlate with a more "resting" memory phenotype for DP versus the perhaps more "activated" CD49a SP. We have previously reported that the CD49a SP subset has a number of features that correlate with a more effector-like phenotype such as having a higher frequency of Granzyme B and perforin double positive cells, poised for cell killing (5).…”

“…In the lungs, T RM are critical for protection against influenza and respiratory syncytial virus, even in the absence of antibodies specific for those viruses (3, 4). T RM have been shown to act as both antigen-specific sentinels linking the innate and adaptive immune systems as well as cytotoxic mediators themselves (5). This functional capacity makes them important players in immunity across multiple organ systems and disease states.…”

“…TRM are heterogenous in terms of integrin expression, migration, effector potential, and gene expression (5). Furthermore, the functions of different CD8 T cell subsets have been linked with distinct metabolic pathways.…”