The Emerging Roles and Therapeutic Potential of Unconventional T Cells in Sepsis

Sepsis represents a dynamic, dysregulated host immune response to infection in which unconventional T cells-γδ T cells, mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and double-negative T cells-actively shape the balance between early hyperinflammation and subsequent immune paralysis across time and tissues. These cells employ unique antigen recognition mechanisms to trigger rapid immune responses. γδ T cells facilitate early pathogen elimination and immune regulation, whereas MAIT cells detect microbial metabolites and modulate the systemic inflammation. NKT cells balance immune homeostasis through dual pro- and anti-inflammatory cytokine production. This review classifies these subsets and examines their sepsis-related functions alongside immunotherapies targeting them, such as cytokine manipulation, immunomodulators, and checkpoint inhibitors. Elucidating the precise mechanisms underlying sepsis could advance therapies that restore immune equilibrium and potentially improve clinical outcomes. Future studies should unravel the interactions between unconventional T cells and broader immune networks while translating the findings into practical treatments. Understanding the dynamic roles of these cells provides pathways for tailored interventions in sepsis management.