Unexplored Domain: The Unconventional T Cells in the Male Genitourinary Tract and Related Diseases

The male genitourinary tract develops a sophisticated immune microenvironment within individual organs and across different organs to maintain tolerance toward germ cells and defense against invasive pathogens, a network orchestrated by diverse immune cells including a special T cell subset termed unconventional T cells. Unconventional T cells, mainly encompassing γδ T cells, natural killer T (NKT) cells, and mucosal-associated invariant T (MAIT) cells, exhibit non-classical antigen recognition, integrate features of innate and adaptive immunity, and manifest tissue-specific functional specialization. Despite their crucial roles in local mucosal immunity and inflammatory regulation, the systematic characterization of these unique T cell subgroups within the male genitourinary system remains largely underexplored. To this end, our comprehensive review systematically summarized knowledge regarding the subsets, distribution, and functions of unconventional T cell populations across the anatomical regions of the male genitourinary tract-findings derived from multimodal methodologies such as immunohistochemical analyses, multicolor flow cytometry, and the latest insights from single-cell transcriptomic sequencing. Moreover, we elucidated the disparities of unconventional T cells in peripheral blood, urine and semen under physiological and pathological conditions, and discussed their clinical significance as promising biomarkers and therapeutic potential in diseases such as male genitourinary tract infection and immune-related infertility.