Influenza-Specific Lung-Resident Memory CD8+ T Cells

Abstract

Despite the availability of seasonal vaccines, influenza A (IAV) prevails as a leading cause of respiratory infection worldwide. Current vaccination efforts aim at increasing protection against heterologous and potentially pandemic IAV strains. Lung-resident CD8⁺ T cells (Trm) generated upon IAV infection are vital for heterosubtypic immunity to IAV reexposure and provide quick and robust responses upon reactivation. Yet, protection wanes with time as lung Trm cell numbers decline, a contrasting feature with Trm cells at other mucosal sites such as the skin. In this review, we discuss current data on lung Trm compared to Trm cells in other tissues. Furthermore, major knowledge gaps in the generation and maintenance of IAV-specific lung Trm are addressed and mechanisms that may contribute to their decline are discussed. Further understanding in the mechanisms that govern effector function versus immunopathology is paramount for future IAV vaccine design in enhancing durability of lung Trm cells.

Figure 1.

Proposed factors that contribute to lung tissue-resident memory T (Trm) cell generation and maintenance. Upon influenza infection, Trm cells derived from T memory precursors (Tmp) populate the lung interstitium and airways, whereas effector memory T (Tem) cells can convert to Trm in the lung to help sustain the lung Trm cell population. Factors that govern the generation of Trm from Tmp and Tem cells in the circulation and their maintenance in the lung remains unclear. However, studies point toward several proposed mechanisms for generation and/or maintenance, which include the type of antigen, TNF, interleukin (IL)-33, and/or TGF-β production, specific antigen-presenting cells (APCs) such as CD103 dendritic cells (DCs), T-cell receptor (TCR) affinity, and transcription factors Blimp-1, Runx3, and/or Notch, and specific chemokine receptors such as CXCR3 and CXCR6.

Figure 2.

Potential mechanisms in lung tissue-resident memory T (Trm) cell decline. Influenza-induced lung Trm cells are not maintained long term concomitant with a gradual loss of protection. Mechanisms that have been proposed that limit the size of this population include interleukin (IL)-10 production, Treg-mediated immunosuppression, oxidative metabolism, oxygen tension, mammalian target of rapamycin (mTOR) signaling, and signaling via the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis.