Tissue-Resident Macrophages Limit Pulmonary CD8 Resident Memory T Cell Establishment

Tissue resident memory CD8 T cells (T(RM)) serve as potent local sentinels and contribute significantly to protective immunity against intracellular mucosal pathogens. While the molecular and transcriptional underpinnings of T(RM) differentiation are emerging, how T(RM) establishment is regulated by other leukocytes in vivo is largely unclear. Here, we observed that expression of PPAR-γ in the myeloid compartment was a negative regulator of CD8 T(RM) establishment following influenza virus infection. Interestingly, myeloid deficiency of PPAR-γ resulted in selective impairment of the tissue-resident alveolar macrophage (AM) compartment during primary influenza infection, suggesting that AM are likely negative regulators of CD8 T(RM) differentiation. Indeed, influenza-specific CD8 T(RM) cell numbers were increased following early, but not late ablation of AM using the CD169-DTR model. Importantly, these findings were specific to the parenchyma of infected tissue as circulating memory T cell frequencies in lung and T(CM) and T(EM) in spleen were largely unaltered following macrophage ablation. Further, the magnitude of the effector response could not explain these observations. These data indicate local regulation of pulmonary T(RM) differentiation is alveolar macrophage dependent. These, findings could aid in vaccine design aimed at increasing T(RM) density to enhance protective immunity, or deflating their numbers in conditions where they cause overt or veiled chronic pathologies.