OX40 Ligand and CD30 Ligand Are Expressed on Adult but Not Neonatal CD4+CD3− Inducer Cells: Evidence That IL-7 Signals Regulate CD30 Ligand but Not OX40 Ligand Expression

Abstract

In this report, we have examined the expression of the T cell survival signals, OX40 ligand (OX40L) and CD30 ligand (CD30L) on CD4+CD3−CD11c−B220−IL-7Rα+ inducer cells from birth to adulthood in mice. We found that adult but not neonatal inducer cells expressed high levels of OX40L and CD30L, whereas their expression of TNF-related activation-induced cytokine (TRANCE) and receptor activator of NF-κB (RANK) was comparable. The failure of neonatal inducer cells to express the ligands that rescue T cells helps to explain why exposure to Ag in neonatal life induces tolerance rather than immunity. The expression of OX40L and CD30L on inducer cells increased gradually in the first few weeks of life achieving essentially normal levels around the time mice were weaned. We found that IL-7 signaling through the common cytokine receptor γ-chain was critical for the optimal expression of both TNF-related activation-induced cytokine and CD30L but not OX40L. Furthermore, glucocorticoids, which potently suppress T effector function, did not influence the expression of OX40L and CD30L in the presence of IL-7.

Neonatal and Adult CD4+CD3− Cells Share Similar Gene Expression Profile, and Neonatal Cells Up-Regulate OX40 Ligand in Response to TL1A (TNFSF15)

“…When we investigated the presence of these cells in neonatal tissues, we found a similar population: however, OX40L and CD30L, the T cell survival molecules, were lacking (3). These studies demonstrated that the expression of OX40L and CD30L was regulated independently: IL-7 signals were important for CD30L but not OX40L expression (3).…”

“…These cells are located in B follicles but also T cell areas, especially the outer T zone. In B follicles they are attached to the T cells that select germinal center (GC) 3 B cells, and in the absence of OX40 and CD30 signals, GC T cells fail to survive, with consequent failure of affinity maturation of the Ab responses (2). Even more significantly, T cell memory for Ab responses is abrogated in OX40 and CD30 double-deficient mice (2), and we have speculated that memory T cells are normally maintained by their associations with these cells in the outer T zone.…”

Splenic stromal cells mediate IL‐7 independent adult lymphoid tissue inducer cell survival

“…Current data indicate that IL-7 improves embryonic LTi survival. Our previous studies have demonstrated that LTi persist in the adult spleen of IL-7 À/À and gc À/À mice [18]. In this study we identified IL-7Ra 1 and IL-7Ra where they interact with VCAM-1 1 T-zone stroma which express podoplanin.…”

Modulation of TNFSF expression in lymphoid tissue inducer cells by dendritic cells activated with Toll-like receptor ligands

“…It is known that OX40L and TRANCE expression on LTi cells is upregulated by TL1A, a TNF-like ligand (25), whereas DCs activated with TLR ligands do not induce TL1A; instead DCs stimulated through FcγR induce TL1A (26). In addition, IL-7 upregulates CD30L on LTi cells, whereas DCs do not express IL-7 and require a 5-day culture (27). Although many studies have shown that DCs activated with TLRs express IL-23 (21,22), we confirmed that IL-23 does not upregulate OX40L expression (28) but instead induces a large amount of IL-22 secretion to promote TH17 responses.…”

“…Cell suspensions for the isolation of LTi, DCs, and B cells were made from the spleens of 6-week-old C57BL/6 mice, as described previously (27). Briefly, spleens were cut into small fragments and then cultured in serum-free RPMI containing 5 mg/ml of collagenase/dipase (Roche, Mammheim, Germany) for 45 min at 37 o C. Digested fragments were crushed between gauze.…”