Thymic output in human newborns is shaped by environmental exposures and a common TCRD genetic variant

Abstract

Naïve T cell output from the thymus varies across the human lifespan and is a key determinant of health, differing between individuals by age, sex, and genetics. How thymic output is dynamically regulated early in life in response to initial microbial colonization remains unclear. We report longitudinal thymic output dynamics, measured as T cell receptor excision circles (TRECs), in 136 newborns from Stockholm, Sweden. Thymic output increases after birth following initial microbial colonization, peaking at 3-4 mo. Peak height correlates with plasma levels of RANKL and lymphotoxin-α and with a common genetic variant in the TCRD locus previously linked to adult thymopoiesis. B cell lymphopoiesis measured by KRECs reveals divergent dynamics between B and T cell branches of the adaptive immune system in early life. Findings are corroborated by thymic tissue analyses, in which local RANKL secretion correlates with medullary, but not cortical, epithelial cell numbers. These results illuminate the establishment of healthy immune-microbe interactions in early human life.