Natural killer T cells constitutively expressing the interleukin‐2 receptor α chain early in life are primed to respond to lower antigenic stimulation

Abstract

SummaryInvariant natural killer T (iNKT) cells are known to constitutively express the high affinity interlukin-2 receptor a chain (CD25) in neonates, but the functional consequence of this phenotype is unknown. Here, we show that high numbers of CD25-expressing iNKT cells are present early in gestation and represent a significant proportion of the developing immune system. Despite their activated phenotype, neonatal iNKT cells express high levels of the Krüppel-like factor-2, a transcription factor associated with quiescent T cells, and require de novo T-cell receptor and CD28 co-stimulation to proliferate. In contrast to bona fide CD4/CD25-expressing regulatory T cells, neonatal iNKT cells do not suppress T-cell responses, indicating that they do not represent an immunosuppressive cell subset. Evidence that neonatal iNKT cells respond to dramatically reduced amounts of CD1d-restricted antigen compared with adult iNKT cells or T cells, and that their proliferation can be induced in the absence of early interleukin-2 suggest that constitutive expression of CD25 'primes' neonatal iNKT cells to respond rapidly to low amounts of antigen. This unique phenotype, which is distinct from adult iNKT cells, as well as other CD25-expressing activated T or regulatory T cells, may be important to ensure stability of a structurally limited peripheral iNKT-cell repertoire early in life.

In vitro T-cell profile induced by BCG Moreau in healthy Brazilian volunteers

“…Neonatal iNKT cells have an inherent and substantially reduced proliferation threshold, and there is a recent suggestion for a potential role of CD25dimC expression in ensuring survival, stability and expansion of a structurally diverse antigenic receptor iNKT-cell repertoire in early stages. 15 However, there is a unifying belief that neonatal CD25C iNKT cells are not simply activated cells, but rather represent a developmentally distinct subset, and is also supported by the absence of other markers of recent T-cell activation, including CD69 and HLA-DR, 16 which remain to be further evaluated in our system.…”

An Immunological Perspective on Neonatal Sepsis

“…Recent data has shown that intestinal neonatal iNKT cells share unique functional properties in contrast to conventional T cells, intestinal neonatal iNKT cells produce robust Th1 and Th17 responses [44]. In humans, iNKT cells are abundant early on in fetal blood [45], although their tissue of origin had remained unclear until recent data showed that these cells accumulate in the small intestine during the second trimester of gestation [44].…”

Ex vivo purification and characterization of human invariant natural killer T cells

“…With aging, iNKT cell proportions increase in mice (Faunce et al, 2005) whereas studies have shown a decrease in humans, significantly more in males (DelaRosa et al, 2002;Crough et al, 2004;Jing et al, 2007;Ladd et al, 2010). This latter characteristic limits the investigation of iNKT cells in older men and makes it essential to control for age and gender in associations with diseases.…”

“…It is normally only expressed by resting or activated Tregs, or transiently following activation of conventional T cells (Malek, 2008). Expression of CD25 on neonatal iNKT cells is associated with a substantially reduced threshold to proliferation compared to adult iNKT, conventional neonatal or adult T cells and with an apparent initial lack of requirement for IL-2 to drive cells into cycle (Ladd et al, 2010). The reasons underlying this unique phenotype are unclear.…”