The role of cell exhaustion in lepromatous leprosy

Abstract Leprosy is a neglected chronic infectious disease caused by Mycobacterium leprae or M. lepromatosis, representing a public health concern in several low-income countries. In Brazil, most patients develop lepromatous leprosy, a clinical form characterized by poor bacillary control due to T helper 2 cells, M2 macrophages, and accentuated humoral immunity. Despite extensive studies, the complete mechanism of the disease is not fully understood. The evasion mechanisms used by the pathogen likely involve cellular exhaustion, which can arise from chronic antigen stimulation, leading to dysfunction at immune checkpoints, a progressive loss of T lymphocyte effector function, and low production of proinflammatory cytokines. Our study investigated the contribution of cellular exhaustion to the hyporesponsiveness of lepromatous leprosy patients by evaluating the classical markers PD-1 and LAG-3, their ligands PD-L1 and PD-L2, and the functional activity of cells after PD-1 blockade, using flow cytometry, immunofluorescence, and gene expression analyses in both blood and skin. Our work shows for the first time that LAG-3 is increased in the skin lymphocytes of lepromatous patients, as well as membrane-bound and soluble PD-1. Furthermore, its classical ligands, PD-L1 and PD-L2, are more available for interaction in all monocyte subsets in these patients. We also identified that PD-1 blockade induces an increase in IFN-γ+ and TNF+ T lymphocytes. Taken together, our data suggest that exhaustion markers contribute to the hyporesponsive profile of lepromatous patients, and that PD-1 blockade could contribute to the reestablishment of lymphocyte effector action and potentially become part of multidrug therapy in the future.