Alveolar Macrophages Inherently Express Programmed Death-1 Ligand 1 for Optimal Protective Immunity and Tolerance

Abstract

Macrophages play a central role in lung physiology and pathology. In this study, we show in mice that alveolar macrophages (AMs), unlike other macrophage types (interstitial, peritoneal, and splenic macrophages), constitutively express programmed death-1 ligand 1 (PD-L1), thereby possessing a superior phagocytic ability and the capacity to repress CTLs by cis- and trans-interacting with CD80 and programmed death-1 (PD-1), respectively. This extraordinary ability of AMs assures optimal protective immunity and tolerance within the lung. These findings uncover a unique characteristic of AMs and an innate immune function of PD-L1 and CD80 and therefore help in the understanding of lung physiology, diseases, and PD-L1/PD-1-based immunotherapy.

Figure 1.

AMs inherently express PD-L1. (A) Specific expression of PD-L1 on the AMs but not IMs, PMs or SMs of FVB/N mice (n = 6). (B) Specific expression of PD-L1 on the AMs but not IMs of BALB/c mice (n = 3). (C) Specific expression of PD-L1 on the AMs but not IMs of C57BL/6 mice (n = 3). Student’s t test was performed (two tailed, paired) and data represent means ± SEM in (A-C). *P < 0.05; **P < 0.01; ns, not statistically significant.

Figure 2.

PD-L1 grants AMs high CTL suppression ability. (A) PD-L1-dependent repression of CD8⁺ T-cell activity by AMs (n ≥ 4). (B) PD-L1-dependent decrease of CD8⁺ T cells by AMs (n ≥ 4). Student’s t test was performed (two tailed, unpaired) and data represent means ± SEM. **P < 0.01.

Figure 3.

PD-L1 optimizes AM phagocytosis. (A) Superior phagocytic ability of AMs in comparison to IMs (n = 6). (B) No PD-L1 expression on the AMs of PD-L1 deficient (PD-L1^KO) mice. (C) Decreased phagocytic ability of PD-L1^KO AMs (n >= 7). Student’s t test was performed (two tailed, unpaired) and data represent means ± SEM in (A, C). **P < 0.01.

FIGURE 4.

PD-L1 interacts with CD80 in cis to boost AM phagocytosis. (A) CD80 expression on the AMs of wild type (WT) but not CD80 deficient (CD80^KO) mice. (B) Co-localization of PD-L1 and CD80 on AMs. (C) Decreased phagocytic ability of CD80^KO AMs (n = 16). (D) High phagocytic ability of AMs expressing high CD80 on the surface (n = 6). (E) PD-1 expression on AMs (n = 6). (F) Increased co-localization of PD-L1 and PD-1 on CD80^KO AMs. (G) Enhanced phagocytic ability of AMs by PD-1 deletion (n = 6). Scale bar: 1 μm. Student’s t test was performed (two tailed, unpaired for C, F, G and paired for D, E) and data represent means ± SEM. **P < 0.01.