Tissue- and age-specific adaptations of human γδT cells in early life

Abstract

γδT cells are unconventional T lymphocytes which seed peripheral tissues in early life. They provide frontline anti-pathogen, anti-cancer and homeostatic responses, rapidly initiated in response to signals of cellular stress independent of MHC-recognition. However, the role of γδT cells in humans has been difficult to assess given their purported tissue residency. Using tissues obtained from organ donors, we conducted flow cytometry, TCR-sequencing, and stimulation assays on γδT cells isolated from blood, spleen, lung, intestines and lymph nodes (LN) to create an ‘atlas’ across the human body throughout life. γδT cells were enriched in the blood, spleen, lung, and jejunum in early life, whereas LN proportions were maintained at low levels. Vδ1 and Vδ2 γδT cell subsets also exhibited tissue- and age-specific phenotypes: Vδ1 cells predominated in all organs in infancy except the lung. They were ‘naïve-like’, acquiring a mature phenotype with age, whereas Vδ2 possessed an effector memory signature, even in donors a few days old. Functionally, Vδ2 cells produced IFNγ, TNFα, GzmB and perforin at high levels in childhood. By contrast, Vδ1 cells favored Areg production during infancy but acquired a cytotoxic profile into adulthood. TCR analysis revealed clonal expansion in mucosal organs, whereas lymphoid sites had increased diversity in early life. Despite this site-specific clonal expansion, V-chain usage was stably distributed across organs and did not show the tissue-specific biases seen in mice. Our analyses reveal that γδT cells may play an outsized role in pediatric tissue immune responses and identify potentially divergent roles of specific subsets that contribute to tissue immunity during the most vulnerable years of life.