Intestinal CD8⁺ T cell responses are abundantly induced early in human development but show impaired cytotoxic...

Gastrointestinal viral infections are a major global cause of disease and mortality in infants. Cytotoxic CD8⁺ T cells are critical to achieve viral control. However, studies investigating the development of CD8⁺ T cell immunity in human tissues early in life are lacking. Here, we investigated the maturation of the CD8⁺ T cell compartment in human fetal, infant and adult intestinal tissues. CD8⁺ T cells exhibiting a memory phenotype were already detected in fetal intestines and increased after birth. Infant intestines preferentially harbored effector CCR7^-CD45RA^-CD127^-KLRG1^+/- CD8⁺ T cells compared to tissue-resident memory CD69⁺CD103⁺CD8⁺ T cells detected in adults. Functional cytotoxic capacity, including cytokine and granzyme B production of infant intestinal effector CD8⁺ T cells was, however, markedly reduced compared to adult intestinal CD8⁺ T cells. This was in line with the high expression of the inhibitory molecule PD-1 by infant intestinal effector CD8⁺ T cells. Taken together, we demonstrate that intestinal CD8⁺ T cell responses are induced early in human development, however exhibit a reduced functionality. The impaired CD8⁺ T cell functionality early in life contributes to tolerance during foreign antigen exposure after birth, however functions as an immune correlate for the increased susceptibility to gastrointestinal viral infections in infancy.