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

Abstract

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.

Keywords: CD169; CD69; CD8 T cell differentiation; PPAR-γ; alveolar macrophage; influenza; tissue-resident memory.