Metallothioneins reprograms T cell response towards pulmonary Histoplasma capsulatum through altering their metabolic profile

Abstract Histoplasma capsulatum (Hc) is a dimorphic fungus that is affected by environmental temperature. Hc is distributed worldwide. When inhaled, the microconidia and spores reach the lung and are converted to the pathogenic yeast phase within the phagosomes of macrophages. The Hc replicates intracellularly until these phagocytes are activated by cytokines, typically from activated T cells. Excluding iron, the effect of trace metals on Hc interaction with innate immune cells has been inadequately studied. The cells’ metabolic processes are altered, and the cytokine macro/microenvironment change in the pathogen’s face. Zn2+ metalloproteins constitute about 10% of the mammalian proteome, and many transcription factors and enzymes use this metal. Metalloproteins are linked to many energy-producing pathways, including carbohydrate metabolism, amino acid metabolism, and the redox chain. Our experiments showed that ablation of Metallothioneins 1 and 2 (MT1/2) decreases the immune system’s ability to clear Hc from the lungs. The numbers of T cells are not affected by the MT1/2 ablation; rather, the cells’ activity is decreased. MT1/2 ablated dendritic cells (DC) are not defective. MT1/2 ablated CD4 T cells show an alternative metabolic profile. MT1/2 ablated CD4 T cells show a decrease in their genome acetylation.