Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity

Abstract

Lung resident memory (Trm) CD8 T cells induced by influenza A virus (IAV) are pivotal for providing heterosubtypic immunity, but are not maintained long term, causing gradual loss of protection. This contrasts sharply with long-term maintenance of Trm induced by localized infections of the skin and other tissues. Here we show that the decline in lung Trm is determined by an imbalance between apoptosis and lung recruitment and conversion to Trm of circulating memory cells. At the cellular level, circulating effector memory (Tem) rather than central memory (Tcm) cells are the precursors for conversion to lung Trm. Time-dependent changes in expression of genes critical for lymphocyte trafficking and Trm differentiation, in concert with enrichment of Tcm, diminish the capacity of circulating memory CD8 T cells to form Trm with time, explaining why IAV-induced Trm are not stably maintained. Importantly, systemic booster immunization, through increasing the number of circulating Tem cells, increases lung Trm, providing a potential new avenue for future IAV vaccines.

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…63,75 The maintenance of CD8 + memory compartment in the lung requires continuous recruitment of circulating memory T cells. 76,77 In contrast to lung T RM differentiation during the acute phase of influenza virus infection, at the memory phase, previously infected lung is permissive to de novo T RM differentiation from circulating T EM cells in a cognate antigen-independent, but IL-33 and TNF-dependent manner.…”

“…76,77 In contrast to lung T RM differentiation during the acute phase of influenza virus infection, at the memory phase, previously infected lung is permissive to de novo T RM differentiation from circulating T EM cells in a cognate antigen-independent, but IL-33 and TNF-dependent manner. 75 The waning of lung T RM cells is caused by the increase of circulating T CM and decrease of T EM , and therefore the decline of continuous T RM induction.…”

“…However, there is one piece of observation needed to be reconciled. Considering that T EM cells continuously migrate and differentiate into lung T RM cell after influenza viral infection, 75 it seems counterintuitive that seven weeks of parabiosis does not lead to significant de novo lung T RM formation in a similar animal model. 47 One possible explanation may be that parabiosis surgery itself causes unexpected inflammation and tissue damage.…”

“…133 Once entry into peripheral non-lymphoid tissues, local cytokines such as TGF-β, IL-33 and TNF cooperate to extinguish the expression of both Klf2 and its target S1pr1 , which potentiates the retention of T RM cells in the tissue. 46,75,88 Mechanistically, PI3K/Akt pathway is activated by cytokine signals to inhibit the expression of transcription factor Foxo1 and therefore enforce the down-regulation of K1f2 46 Various combinations of pro-inflammatory cytokines can suppress the expression of Klf2 in activated CD8 + T cells in vitro, including type I IFN, IL-12 and IL-18. 46,88 However, type I IFN does not significantly alter T RM differentiation 44 and IL-12 inhibits early differentiation and promotes long-term maintenance of gut T RM .…”

Repeated Antigen Exposure Extends the Durability of Influenza-Specific Lung-Resident Memory CD8+ T Cells and Heterosubtypic Immunity

“…It has been well documented in humans and rodent models that influenza-specific CD8 + T cells targeting conserved internal proteins of the virus can control virus titers and limit disease development in the absence of neutralizing antibodies (Altenburg et al, 2015; Kreijtz et al, 2007; McMichael et al, 1983; Sridhar et al, 2013). Recent research suggests that the population of lung-resident CD8 + T cells (T rm ) induced by primary influenza infection plays a critical role in such heterosubtypic immunity (HI) (Hogan et al, 2001; Slütter et al, 2017; Wu et al, 2014). Thus, inducing a potent and long-lasting influenza-specific T rm population should be considered as a potentially useful vaccination target.…”