Tissue resident memory T cells in the respiratory tract

Abstract

Owing to their capacity to rapidly spread across the population, airborne pathogens represent a significant risk to global health. Indeed, several of the past major global pandemics have been instigated by respiratory pathogens. A greater understanding of the immune cells tasked with protecting the airways from infection will allow for the development of strategies that curb the spread and impact of these airborne diseases. A specific subset of memory T-cell resident in both the upper and lower respiratory tract, termed tissue-resident memory (Trm), have been shown to play an instrumental role in local immune responses against a wide breadth of both viral and bacterial infections. In this review, we discuss factors that influence respiratory tract Trm development, longevity, and immune surveillance and explore vaccination regimes that harness these cells, such approaches represent exciting new strategies that may be utilized to tackle the next global pandemic.

Fig. 1. Respiratory tract Trm generation and maintenance.

1) Upon respiratory pathogen encounter, dendritic cells (DCs) migrate to the mediastinal lymph node to activate naive CD8⁺ T cells for which effector CD8⁺ T cells then migrate into the nasal or lung tissue for their conversion into Trm. 2) In the lung, local tissue factors including antigen, cytokines, co-stimulation, and cellular interactions together with a tissue-resident transcriptional profile drive the formation of Trm. The development of nasal CD8⁺ Trm is independent of local antigen or TGFβ cytokine production. 3) The maintenance of parenchyma lung CD8⁺ Trm has been proposed to be dependent on replenishment from circulating CD8⁺ Tem cells or via  in situ homeostatic proliferation of lung CD8⁺ Trm in sites of tissue regeneration called repair-associated memory depots (RAMDs). CD8⁺ Trm in such sites were shown to replenish the pro-apoptotic airway CD8⁺ Trm compartment via a CXCR6-CXCL16 axis. The maintenance of lung CD4⁺ Trm is less studied, though IL-7 has been shown to be required for their maintenance.