Tem replenish lung Trm: When input does not match output, lung-resident memory T cells decay

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Tissue-resident memory CD8+ T cells (Trm) are a non-recirculating, self-sustaining class of memory T cells lodged within a variety of peripheral tissues that play a critical role in local immune protection. Characteristically, Trm persist within peripheral tissues with minimal decay, providing prolonged local protection against re-infection. The notable exception is Trm located in the lung, which wane with time, gradually leaving the airways susceptible to re-infection.1 It is unclear why lung Trm decay over time; however, the numerical erosion of the population is likely driven by a need for strict numeric limitations, given the sensitivity of this site to immunopathology. Improved understanding of factors that are important in the maintenance of lung Trm and the development of strategies that prolong the longevity of this population represent important steps in the development of vaccination strategies that provide long-term protection against inhaled pathogens. In a new study in Science Immunology, Slutter et al.2 provide an explanation for the decline of lung Trm and, importantly, describe an exciting new strategy to prolong the longevity of the lung Trm pool and, in turn, immunity to respiratory pathogens.
To provide insight into why lung Trm undergo attrition, the authors set out to determine how lung Trm are maintained. Using a mouse model of influenza virus infection the authors revealed that lung Trm required continual replenishment from the circulating memory CD8+ T-cell pool to persist. The gradual decay in lung Trm numbers resulted from an imbalance that occurred when the apoptotic loss of lung Trm was no longer matched by the replenishment from the circulating memory CD8+ T-cell pool. The authors showed that within the circulating memory CD8+ T-cell compartment, it was the effector memory CD8+ T cell (Tem) subset that migrated into the lung and differentiated into Trm. The loss of Tem from the circulating memory CD8+ T-cell compartment that occurred over time depleted the system of lung Trm precursor cells, and this underlies the decay of lung Trm (Figure 1). Importantly, the authors showed that by simply boosting Tem numbers they could prolong the longevity of the lung Trm pool.
Slutter et al. made the interesting observation that circulating Tem infiltrated into the lung and differentiated into lung Trm more effectively following transfer into mice recovering from a prior influenza virus infection compared to that observed following transfer into naive recipients. These data suggest that prior infection within the lung conditions the tissue microenvironment, making it more permissible for lung Trm generation. The authors examined the factors within the previously infected lung tissue that promoted the development of lung Trm; specifically they addressed the role of residual antigen within the lung tissue and the local cytokine milieu.
Influenza viral antigen is known to persist within the lung for many months after the clearance of the acute infection.3,4 To investigate if residual influenza antigen in the lung facilitated the maintenance of the lung Trm pool, Slutter et al. transferred transgenic Tem into mice that were previously infected with an influenza virus strain that encoded either the cognate epitope recognized by the transgenic Tem pool or the parental strain of influenza virus, which did not encode this epitope. As the proportion of Tem that converted into Trm within the lung in both cohorts were equivalent, the authors ruled out the requirement for local antigen recognition in the maintenance of the lung Trm pool.
The presence of antigen within the tissue microenvironment does have a profound impact on CD8+ Trm formation.
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