Stimulation of the immune system by pathogens, allergens, or autoantigens leads to differentiation of CD4+ T cells with pro- or anti-inflammatory effector cell functions. Based on functional properties and expression of characteristic cytokines and transcription factors, effector CD4+ T cells have been grouped mainly into Th1, Th2, Th17, and regulatory T (Treg) cells. At least some of these T cell subsets remain responsive to external cues and acquire properties of other subsets, raising the hope that this functional plasticity might be exploited for therapeutic purposes. In this study, we used an Ag-specific adoptive transfer model and determined whether in vitro-polarized or ex vivo-isolated Th1, Th17, or Treg cells can be converted into IL-4–expressing Th2 cells in vivo by infection of mice with the gastrointestinal helminth Nippostrongylus brasiliensis. Th1 and Th17 cells could be repolarized to acquire the expression of IL-4 and lose the expression of their characteristic cytokines IFN-γ and IL-17A, respectively. In contrast, both in vitro-generated and ex vivo-isolated Treg cells were largely resistant to repolarization. The helminth-induced conversion of Th1 or Th17 cells into Th2 cells may partially explain the inverse correlation between helminth infection and protection against autoimmune disorders.

Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7− and α4β7+ lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer’s patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46− group 3 ILCs in wild-type and even in Il7−/− mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer’s patches development by targeting lymphoid progenitor cells during fetal and adult life.

Dendritic cells (DCs) are considered to be the major APCs with potent activity for priming of naive CD4 and CD8 T cells. However, T cell priming can also be achieved by other APCs including macrophages, B cells, or even nonhematopoietic cell types. Systemic low-dose infection of mice with lymphocytic choriomeningitis virus (LCMV) results in massive expansion of virus-specific CD4 and CD8 T cells. To determine the role of DCs as APCs and source of type I IFNs in this infection model, we used ΔDC mice in which DCs are constitutively ablated because of expression of the diphtheria toxin α subunit within developing DCs. ΔDC mice showed lower serum concentrations of IFN-β and IL-12p40, but normal IFN-α levels during the first days postinfection. No differences were found for proliferation of transferred TCR-transgenic cells during the early phase of infection, suggesting that T cell priming occurred with the same efficiency in wild-type and ΔDC mice. Expansion and cytokine expression of endogenous LCMV-specific T cells was comparable between wild-type and ΔDC mice during primary infection and upon rechallenge of memory mice. In both strains of infected mice the viral load was reduced below the limit of detection with the same kinetic. Further, germinal center formation and LCMV-specific Ab responses were not impaired in ΔDC mice. This indicates that DCs are dispensable as APCs for protective immunity against LCMV infection.

Jun activation domain-binding protein 1 (JAB1) regulates ubiquitin-dependent protein degradation by deneddylation of cullin-based ubiquitin ligases and, therefore, plays a central role in regulating proliferation and apoptosis. Because these processes are decisive for B cell development, we investigated JAB1 functions in B cells by establishing a mouse strain with a B cell-specific JAB1 deletion. We show that JAB1 is essential for early B cell development, because the ablation of JAB1 expression blocks B cell development between the pro-B and pre-B cell stages. Furthermore, JAB1 deletion leads to aberrant expression of the apoptosis-triggering protein Fas ligand in pro-B cells. Concomitant B cell-specific overexpression of the antiapoptotic protein Bcl2 partially reverses the block in B cell development; rescued JAB1-deficient B cells reach the periphery and produce protective class-switched Abs after Borrelia burgdorferi infection. Interestingly, B cell-rescued mice exhibit no germinal centers but a striking extrafollicular plasma cell accumulation. In addition, JAB1 is essential for Bcl6 expression, a transcriptional repressor required for germinal center formation. These findings identify JAB1 as an important factor in checkpoint control during early B cell development, as well as in fate decisions in mature Ag-primed B cells.