Invited Speakers

Immune cells are continuously exchanged throughout healthy life, and even more so during disease. Hematopoietic Stem Cells (HSCs) are able to give rise to all types of blood and immune cells, they also enable bone-marrow transplant that is leading stem-cell's clinical usage. Surprisingly, relatively little is known about HSCs during acute infection. In addition, obtaining of compatible primary HSCs is still limiting the treatment of patients. We have generated and analyzed an extensive set of expression-profiles covering most of the murine hematopoietic system, to identify HSC-specific genes. Following previous success of reprogramming, we cloned few dozens of HSC transcription-factors. Transient overexpression of these factors in committed progenitors endowed them with extended self-renewal and multipotency. We have further identified 6 "core-factors" that can reprogram adult mouse blood cells back into transplantable "induced-HSCs". This novel direct reprograming of adult cells into adult stem-cells is being translated into human, and already provides new insights into HSC's regulation during normal and malignant states. In parallel, we have generated an HSC reporter mouse by targeting a fluorescent protein into the Fgd5 locus. The Fgd5-mCherry proved highly specific, enabling identification and isolation of functional HSCs solely by this endogenous reporter. While previous studies have reported a paradox of reduced transplantation-activity of the bone-marrow upon immune-stimulation with an increase of immune-phenotype HSCs, we do observe a clear reduction of the frequencies, and total numbers, of Fgd5-mCherry+ HSCs upon either pIC or LPS stimulation. Understanding the dynamics of activated stem-cells will shed new light on the progressive immune system in action.

Many studies, including those coming from our lab, have shown that only a limited number of chemokines are key drivers of inflammation, among them the CXCR3 ligands CXCL9 and CXCL10, but not CXCL11. Twelve years ago we showed that CXCL10 is a key driver of inflammatory autoimmunity since aside of attracting effector T cells to site of inflammation, it also drive the polarization of non-polarized CD4+ T cells into effector Th1 cells. Surprisingly transgenic mice lacking CXCR3 display an aggravated manifestation of different autoimmune disease. We now show that while CXCL9 and CXCL10 induce effector Th1/Th17 cells to promote inflammation CXCL11, with a relatively higher binding affinity to CXCR3 induces FOXP3-negative IL-10high Tregs resembling Tr1 cells. This may explain, in part, why mice lacking CXCR3 display aggravated form of autoimmunity. We also show that CXCL9/CXCL10 transmit a different signaling cascade than CXCL11 via the same CXCR3 receptor, which results in these diverse biological activities. To explore the therapeutic implications of this study we generate a CXCL11-Ig fusion protein that when administered during relapsing experimental autoimmune encephalomyelitis not only suppressed the first episode, but also prevented the subsequent relapse. Tr1-like cells isolated from treated donors could transfer disease suppression. Genetic analyses reviled that even thought these cells are similar to “classical” Tr1 cells they display a novel gene-signature.
We are now using FOXp3-GFP reporter mice to identify a reciprocal chemokine that potentiates FOXp3+ T cells and explore its possible use for therapy of inflammatory autoimmunity and graft Vs host diseases (GVHD).
These data, together with our pervious observations showing that during an ongoing inflammatory process CXCL12 polarizes IL-10high Tr1 cells (Meiron et al, JEM 2008) provide a new perspective on our understanding of the biological properties of chemokines and suggests novel therapeutic strategies to combat autoimmunity and GVHD.

Ubiquitin and Ubiquitin-like (Ubl) modifications has emerged as a major regulatory mechanism in a variety of fundamental cellular processes, such as signal transduction, cell division and differentiation.  E3 ligases like TRAF, ITCH, A20 and GRAIL have been implicated in immune regulation such as the development of lymphocytes, antigen presentation, immune evasion, as well as autoimmunity. Aberrations in the function of these E3s  are associated with immune system pathologies, yet we still lack understanding of their dynamics and regulation in the cell.
Recently we developed a PTM profiling approach which allows large-scale detection of protein modifications in mammalian systems.  This system offers a novel opportunity to detect changes in PTM patterns in response to specific signal, in disease and across cell types. Further, it offers a new molecular dimension by which the plasticity of immune regulation may be investigated.