Unconventional T Cells in Infectious Diseases and Cancer

This research topic explores the biological functions and immunological roles of unconventional T cells in infectious diseases and cancer. Unlike classical MHC-restricted CD4⁺ and CD8⁺ T cells, these subsets, including group 1 and group 2 CD1-restricted T cells, γδ T cells, and mucosal-associated invariant T (MAIT) cells, recognize non-peptide antigens such as lipids, metabolites, and small-molecule intermediates. These cells bridge innate and adaptive immunity through rapid responses to microbial infection and tumor growth, producing cytokines that influence downstream immune activity. Recent work suggests they play important roles in infection control, inflammation, and tumor progression. However, their activation mechanisms, effector functions, and therapeutic applications remain incompletely understood, making this an important area for current review and discussion.

This Research Topic highlights the immunological roles and therapeutic potential of unconventional T-cell populations, with a particular focus on CD1-restricted T cells (groups 1 and 2), γδ T cells, and mucosal-associated invariant T (MAIT) cells in infectious diseases and cancer. These subsets are increasingly recognized as key intermediaries between innate and adaptive immunity, yet important questions remain regarding their modes of antigen recognition, effector functions, and contributions to protective versus pathogenic responses across different disease settings.

This collection brings together recent progress in defining the activation pathways, antigen presentation mechanisms, and tissue distribution of unconventional T cells. Special attention is given to advances made possible by single-cell genomics and transcriptomics, structural analyses of TCR-ligand interactions, and humanized mouse models that more faithfully reflect human immune responses. By integrating these developments, the collection aims to clarify current knowledge and identify promising directions for translational research, including vaccine design and immunotherapeutic strategies that leverage the unique recognition properties and rapid response capabilities of these T-cell subsets.

This Research Topic invites contributions that advance knowledge of unconventional T-cell biology and translational applications in infection and cancer. We seek submissions addressing:

• Antigen recognition mechanisms in CD1-restricted T cells, γδ T cells, and MAIT cells
• Functions in host defense, inflammation, and tumor immunity
• Interactions with innate and adaptive immune cells
• Relationships with tissue and tumor microenvironments
• Use of advanced methodologies including single-cell and spatial transcriptomics, structural immunology, or humanized mouse models
• Translational research on vaccines or immunotherapies targeting these populations

We welcome Original Research, Reviews, Mini-Reviews, Hypothesis and Theory articles, and Brief Research Reports that integrate basic and translational perspectives.