T-cell exhaustion in leprosy: molecular mechanisms and therapeutic implications

One of the immunological defects in leprosy, particularly in the lepromatous form, is the progressive impairment of T-cell effector functions caused by the chronic exposure to Mycobacterium leprae . This review aims to highlight the role of T-cell exhaustion, molecular mechanisms, cellular pathways, and clinical implications of T-cell exhaustion in leprosy. We discuss the existing evidence on exhaustion markers like Programmed Cell Death Protein 1(PD-1), Cytotoxic T-lymphocyte associated protein 4, (CTLA-4), Lymphocyte-activation gene 3 (LAG-3), T-cell Immunoglobulin and Mucin-domain containing-3 (TIM-3), and T cell Immunoreceptor with Ig and ITIM domains (TIGIT), their networks, and how they can be used in therapeutic interventions through checkpoint blockade and immunomodulation. A comprehensive literature search was carried out over the past 20 years on PubMed, Google Scholar, and Ovid. Articles published in English, original research, review, and appropriate experimental studies were eligible for inclusion. For this review, studies were prioritized that are related to immunological dysfunction, checkpoint pathways, chronic antigen stimulation, and host immune responses in leprosy. Insights into T-cell exhaustion in leprosy deepen our understanding of host-pathogen interactions and provide promising opportunities to develop new treatment methods to enhance the patients’ treatment strategies and prevent disability.