CD30 Ligand/CD30 Plays a Critical Role in Th17 Differentiation in Mice

Abstract

A CD30 ligand (CD30L; CD153) and its receptor, CD30, is a membrane-associated glycoprotein belonging to the TNF superfamily and TNFR superfamily. These were expressed preferentially by activated CD4+T cells. In this paper, we show that CD44lowCD62hiCD4+ T cells from CD30L−/− or CD30−/− mice exhibited impaired differentiation into Th17 cells but an increased ability to produce IL-2 after in vitro culture under Th17-polarizing conditions. Neutralization with IL-2 by anti–IL-2 mAb partly restored the ability of Th17 differentiation in CD30L−/− or CD30−/− T cells. Stimulation via CD30L by immobilized anti-CD30L mAb suppressed IL-2 production by CD30−/−CD4+ T cells, indicating that the reverse signal to CD30L is responsible for downregulation of IL-2 production. In vivo Th17 differentiation of CD30L−/−CD4+CD45RBhigh T cells was also impaired after transfer into SCID mice, whereas CD30L+/+CD4+CD45RBhigh T cells normally differentiated into Th17 cells in CD30L−/−SCID mice. The results of these studies demonstrate that CD30L/CD30 signaling executed by the T-T cell interaction plays a critical role in Th17 cell differentiation, at least partly via downregulation of IL-2 production.

CD30 Ligand Is a Target for a Novel Biological Therapy against Colitis Associated with Th17 Responses

“…Furthermore we have recently found that colitis was attenuated in SCID mice to which CD30L 2/2 CD4 + CD45RB high T cells have been transferred, suggesting that CD30L is involved in the pathogenesis of Th1-type colitis (12). In this study, we show that CD30L 2/2 mice were resistant to DSS-induced acute colitis (30) and to chronic colitis induced by multiple cycles of DSS (16).…”

“…We have recently reported that naive CD44 low CD62L hi CD4 + T cells from CD30L 2/2 mice exhibited impaired differentiation into Th17 cells but an increased ability to produce IL-2 after in vitro culture with Th17-polarizing condition (12). To determine whether mCD30-Ig can suppress Th cell differentiation by blocking of CD30L/CD30 signaling, naive CD4 + T cells were sorted from splenocytes of WT mice and cultured with mCD30-Ig in polarizing conditions for Th1, Th2, or Th17 cell differentiation.…”

“…It has recently been reported that CD30L/CD30 signaling plays a role in naturally occurring regulatory T cell (Treg) response in a CD4 + T cell-mediated lethal graft-versus-host disease model (11). We have recently found that CD30L/CD30 signaling executed by the T-T cell interaction plays a critical role in Th17 cell differentiation in vitro and in vivo (12). Thus, CD30L/CD30 signaling may not be directly linked to a physiological step for the differentiation of a specific Th cell subset but may be important for amplification and/or activation of any subset of effector Th cells.…”

Targeted deletion of Traf2 allows immunosuppression-free islet allograft survival in mice

“…Impaired cardiac allograft rejection has previously been observed, with long-term surviving cardiac allografts exhibiting high expression of IL-4 [24,25] and following IL-13 administration in rodents [26], whereas impaired donor-derived IL-13 levels have been correlated with an increased severity of graft-vs-host disease [27]. Furthermore, similar to CD30 -/-CD4 + T cells [28], Traf2TKO CD4 + T cells were unable to differentiate into IL-17 + Th17 cells. Blockade of IL-17 has been shown to prolong cardiac allograft survival [29,30].…”

A matter of life and death: More members of the TNF receptor family join human γδ T lymphocytes

“…The plasticity of gd T cells towards a Th1-and Th2-cell phenotype has previously been explored [9] and CD30 appears to be preferentially expressed in Th2-skewed gd T-cell populations, in agreement with reports claiming CD30 as a specific Th2-cell marker in ab T lymphocytes. In the context of T-helper subset differentiation in general and not just limited to gd T cells murine knockout models have shown the involvement of the CD30-CD30L interaction in Th17-cell differentiation [10]; however, it still remains to be determined whether this interaction also affects the development and function of the newly described IL-17-producing Vg9Vd2 T cells [11].…”