Maternal and Infant Immune Repertoire Sequencing Analysis Identifies Distinct Immunoglobulin and T Cell Receptor Development in Term and Preterm Infants

Abstract

Preterm labor (PTL) is the leading cause of neonatal morbidity and mortality worldwide. While many studies have focused on investigating the maternal immune responses that cause PTL, fetal immune cell activation has recently been raised as an important contributor to the pathogenesis of PTL. Here, we analyzed lymphocyte receptor repertoires in maternal and cord blood from 14 term and 10 preterm deliveries and hypothesized that the high incidence of infection in patients with PTL may result in specific changes in the TCR and BCR repertoires. We analyzed T-cell receptor beta chain (TCR-β) and immunoglobulin heavy chain (IgH) diversity, CDR3 lengths, clonal sharing, and preferential usage of variable (V), diversity (D), and joining (J) gene segments. Additionally, we studied the rates of somatic hypermutation (SHM) in IgH. Overall, the cord blood IgH repertoires had significantly (padj < 0.05) lower rates of SHM and both TCR-β and IgH repertoires had shorter CDR3s compared to maternal blood. When comparing term and PPROM cord blood samples, we found that CDR3 lengths correlated with gestational age, with the shorter CDR3s in preterm neonates suggesting a ‘less developed’ repertoire. Preterm cord blood displayed preferential usage of a number of V genes and J genes. Furthermore, the term maternal repertoires displayed significant preferential usage of TRBV7-8 compared to preterm maternal repertoires. In preterm pregnancies, we observed significantly higher prevalence of convergent clones between mother/baby pairs than in term pregnancies. Together, our results suggest the repertoire of preterm infants displays a combination of immature features yet preferential use of particular genes and convergence with maternal TCR-β clones compared to term infants. While the higher TCR-β diversity might reflect less clonal expansion, the higher clonal convergence between mothers and infants in PTL could represent mother and fetus both responding to a shared stimulus like an infection. These data provide a detailed analysis of the maternal-fetal immune repertoire in term and preterm patients, and contribute to a better understanding of neonate immune repertoire development and potential changes associated with preterm labor.