Unique Transcriptional and Functional Profiles of Neonatal Naïve CD4+ T Cells Expressing KLRG1 2260016

Abstract

Abstract Introduction Human neonates, particularly those born prematurely, are susceptible to severe infections and inflammatory diseases with long-term complications. The immune factors driving these clinical differences are not well understood. Recent evidence suggests that instead of being merely in a generally naïve state, unique neonatal CD4+ T cell subsets may exist in an effector-like state and differentiate more quickly than their adult counterparts. Killer-like Lectin Receptor G1 (KLRG1), an immune checkpoint receptor found on terminally differentiated T cells in adults, has been observed on ∼30% of CD4+ T cells found in cord blood (CB) of healthy neonates. However, little is known about the functional phenotype and transcriptome of these cells, and their clinical significance in neonates is relatively unexplored. Methods We conducted flow cytometry and CITE-seq on CB mononuclear cells obtained from healthy full-term and premature infants. Additionally, persistent respiratory morbidity (PRD) as a function of KLRG1+ CD4+ T cells was examined in a longitudinal cohort of preterm infants. Results The frequency of KLRG1+ CD4 cells positively correlated with gestational age at birth until term corrected age (TGA), then decreased at one year. Preliminary analysis identified a lower risk of PRD in premature infants with higher KLRG1 frequency by TGA. Compared to KLRG1- CD4+ T cells, cord blood KLRG1+ CD4s were mainly naïve, had lower CD38 surface staining, and higher TNF-α and lower IL-8 production following stimulation. KLRG1+ CD4+ T cells expressed higher ANXA1 and FTH1 genes, which suggests peripheral activation or early differentiation. Conclusion Our results suggest that KLRG1 expression on naïve CD4 T cells identifies a functionally distinct CD4+ T cell population present in neonates, whose frequencies are developmentally regulated. Although preliminary analysis suggests a protective role, further investigation into their role and potential mechanism in protection or immunopathology are warranted. Funding Source NIH NIAID HHSN272201200005C (Respiratory Pathogens Research Center) University of Rochester Department of Pediatrics U24AI152176 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)