Ronayne, C. E. | Search bioRxiv

bioRxiv2024

CD4+ T cells recruit, then engage macrophages in cognate interactions to clear Mycobacterium tuberculosis from the lungs.

IFN-{gamma}-producing CD4+ T cells are required for protection against lethal Mycobacterium tuberculosis (Mtb) infections. However, the ability of CD4+ T cells to suppress Mtb growth cannot be fully explained by IFN-{gamma} or other known T cell products. In this study, we show that CD4+ T cell-derived IFN-{gamma} promoted the recruitment of monocyte-derived macrophages (MDMs) to the lungs of Mtb-infected mice. Although the recruited MDMs became quickly and preferentially infected with Mtb, CD4+ T cells rapidly disinfected the MDMs. Clearance of Mtb from MDMs was not explained by IFN-{gamma}, but rather by MHCII-mediated cognate interactions with CD4+ T cells. These interactions promoted MDM expression of glycolysis genes essential for Mtb control. Thus, by recruiting MDMs, CD4+ T cells initiate a cycle of bacterial phagocytosis, Mtb antigen presentation and disinfection in an attempt to clear the bacteria from the lungs.

immunology↗

bioRxiv2022

Trem2 Promotes Foamy Macrophage Lipid Uptake and Survival in Atherosclerosis

Atherosclerotic plaque formation is driven by the continued expansion of cholesterol loaded foamy macrophages within the arterial intima. Foamy macrophages are primarily derived from newly recruited monocytes, but factors regulating monocyte specification toward foamy macrophage differentiation and prolonged survival in plaque remain poorly understood. We used trajectory analysis of integrated single cell RNA-seq data, along with a genome-wide CRISPR screening approach to identify Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) as a candidate regulator for foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up additional oxidized low density lipoprotein (LDL) cholesterol in vitro. Competitive chimera experiments showed that Trem2-deficient macrophages were less competent to form foamy macrophages when competed against Trem2-sufficient macrophages in vivo. In addition, myeloid specific conditional deletion of Trem2 resulted in a dramatic attenuation of plaque progression, even when targeted in established atherosclerotic lesions. This was independent of changes in circulating inflammatory cytokines, monocyte recruitment, or serum cholesterol levels, but due to a reduction in plaque macrophage proliferation and enhanced cell death. Mechanistically, we link Trem2-deficient macrophages with an inability for cells to sense cholesterol loading and failure to upregulate efflux molecules. Accumulation of cholesterol in the endoplasmic reticulum enhanced activation of the ER-stress response that increased susceptibility for cholesterol-toxicity and cell death in foamy Trem2-deficient macrophages. Overall, this study identifies Trem2 as a regulator of foamy macrophage differentiation, atherosclerotic plaque growth, and as a putative therapeutic target for future intervention studies.

immunology↗