Heme: A Novel Driver of Immune Aging
Age-related morbidity, including the increased rate of infectious diseases, cancer, and autoimmune disorders, is driven by the decline in immune potency. The aged immune system is characterized by systemic inflammation and compromised adaptive immunity. T lymphocytes, the cellular arm of the adaptive immune response, are one of the most negatively affected populations. Recently, we made a surprising observation that the functionality of aged T cells depends on the organ they reside in; T cells purified from an aged spleen fail to proliferate, whereas T cells isolated from the lymph nodes of the same donor respond like young cells. Whole-cell proteomics identified heme as a potential driver of this phenotype, as we quantified a significant upregulation of enzymes involved in heme catabolism only in T cells derived from the aged spleen. Why are T cells exposed to heme in the aged spleen? We found age-driven changes in spleen morphology, leading to loss of boundaries between the lymphocyte compartment (white pulp) and the site of red blood cell recycling (red pulp). Strikingly, exposing young T cells to heme ex vivo or to the aged spleen microenvironment in vivo was sufficient to drive multiple, aging-like phenotypes. Previous studies have shown that introducing aged/dysfunctional T cells into a young host promotes aging-like phenotypes in multiple organs. Our studies highlight the intricate relationship between lymphocytes and their immediate microenvironment, emphasizing how age-driven changes in tissue function impact T cell immunity and identify heme as a novel driver of immune dysfunction with aging.