PD‐L2⁺ wound zone macrophage‐like cells display M1/M2‐mixed activation and restrain the effector Th1 responses

Abstract

Depending on the microenvironment conditions, macrophages display phenotypic and functional heterogeneity. This study characterized the programmed cell death-ligand 2 (PD-L2)-expressing macrophage-like cells drained from surgical wound zones, and investigated their influence on helper T (Th) cell responses. Although all CD14 + myeloid cells possessed macrophagelike features, CD206 + and CD163 + cells constituted a specific subpopulation with high PD-L2 expression. There was a modest correlation between the PD-L2 levels on CD206 + macrophages and the amount of interferon (IFN)-c in the drainage fluid. The adhesion-independent macrophages simultaneously presented both classically-activated M1 and alternatively-activated M2 characteristics. CD206 + and PD-L2 + cells were identified with high granularity and size, expressed arginase-1 and costimulatory molecules, had enhanced phagocytic activity and produced reactive oxygen species. The genes associated with macrophage differentiation (MERTK, AXL and TYRO3) were also upregulated. These cells provided costimulation to Th cells; yet, when PD-L2 was blocked, T-cell proliferation and IFNc production were enhanced. Under defined conditions devoid of activation stimuli and matrix adhesion, ex vivogenerated monocyte-derived macrophages displayed limited capacity to stimulate T cells. Upon exposure to IFNc, they significantly upregulated programmed death 1 ligands, especially PD-L2. These cells did not completely abrogate T-cell differentiation; however, PD-L2 checkpoint blockade restored Th1 proliferation and secretion of interleukin-2, tumor necrosis factor-a and IFNc. In conclusion, upregulation of PD-L2 on the wound zone macrophages may constitute a negative feedback loop that restrains the Th1 effector responses and avoids exacerbation of inflammation during tissue healing.

Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF

“…When macrophages are stimulated with IL4 (with or without IL13, which also signals through the IL4Rα; hereafter we used a combination of IL4+IL13 to harmonize the results with previous studies [ Kratochvill et al, 2015b ]), a characteristic gene expression program is activated, which was first described as “alternative activation” ( Gordon & Martinez, 2010 ) and often referred to as “M2.” The physiology of only a handful of M2-associated targets, such as Arg1 and PD-L2, are understood in terms of their relationship to M2 functions in type 2 immunity and metabolic maintenance of OXPHOS, which is essential for the M2 phenotype ( Pesce et al, 2009 ; Huber et al, 2010 ; Gundra et al, 2017 ; Van de Velde et al, 2017 ; Baardman et al, 2018 ; Wang et al, 2018 ; Tavukcuoglu et al, 2020 ). To begin to dissect the influence of TNF on M2 gene expression in molecular terms, we chose one M2 target, Retnla (encoding RELMα), as a paradigmatic gene induced by IL4+IL13 and negatively regulated by TNF ( Kratochvill et al, 2015b ).…”

Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment

“…(2) TAMs secret the immunosuppression cytokines regulate the T cell-induced ant-tumor immunity, including IL-10, IL-6, PGE2, and TGF-beta1 [ 97 ]. (3) TAMs express PD-L1 and PD-L2 and participate exhaustion of CD8 + T cell by cell–cell interaction[ 98 , 99 ].…”

Loss of LXN promotes macrophage M2 polarization and PD-L2 expression contributing cancer immune-escape in mice

“…Interestingly, IRF1 is the key factor of PD-L1 promoter function, while PD-L2 is mainly regulated by STAT1/3 [ 33 ], which also explain our results that only PD-L2 is upregulated in LXN −/− macrophages. It has been reported that PD-1 ligands (PD-Ls) contribute to the M2 polarization and immunosuppressive effects of macrophages [ 48 ], and PD-L2 expression correlated with other established markers for alternatively activated macrophages [ 49 ]. As early as ten years ago, Huber et al reported that PD-L2 appears to be a more specific and distinctive marker for M2, and IL-4 induced the expression of PD-L2 on classically activated macrophages, however, LPS increased the expression of PD-L1 on M2 [ 50 ].…”