CD8⁺ T Cell Functional Exhaustion Overrides Pregnancy-Induced Fetal Antigen Alloimmunization

Pregnancy necessitates physiological exposure, and often re-exposure, to foreign fetal alloantigens. The consequences after pregnancy are highly varied, with evidence of both alloimmunization and expanded tolerance phenotypes. We show that pregnancy primes the accumulation of fetal-specific maternal CD8⁺ T cells and their persistence as an activated memory pool after parturition. Cytolysis and the potential for robust secondary expansion occurs with antigen re-encounter in non-reproductive contexts. Comparatively, CD8⁺ T cell functional exhaustion associated with increased PD-1 and LAG-3 expression occurs with fetal antigen re-stimulation during subsequent pregnancy. PD-L1/LAG-3 neutralization unleashes the activation of fetal-specific CD8⁺ T cells, causing fetal wastage selectively during secondary but not primary pregnancy. Thus, CD8⁺ T cells with fetal alloantigen specificity persist in mothers after pregnancy, and protection against fetal wastage in subsequent pregnancies is maintained by their unique susceptibility to functional exhaustion. Together, distinct mechanisms whereby fetal tolerance is maintained during primary compared with subsequent pregnancies are demonstrated.