A paradoxical role for IFN-gamma in the immune properties of mesenchymal stem cells during viral challenge.

OBJECTIVE: The functional "plasticity" and immune-suppressive effects of human bone marrow (BM)-derived mesenchymal stem cells (MSC) provide them with the potential to be used across allogeneic barriers. The immunosuppressive properties of MSC may be detrimental in a clinical setting in which viral exposure is common. The study hypothesizes that MSC-derived IFN-gamma could offset the immune-suppressive functions of MSC and mediate partial CTL responses during viral infection. METHODS: CTL responses were studied in bioassays with (51)Cr-P815 targets and PBMC (uninfected or infected) as effectors. Immunofluorescence studied the relative expression of CD8(+) cells. Cytokine analyses were performed with microarrays. Roles for IFN-gamma in CTL responses were studied with IFNgammaRI mAb or with MSC knockdown for IFN-gamma by siRNA (pPMSKH1-IFNgamma). RESULTS: MSC showed no significant effect on circulating CTL of healthy subjects. For virus-induced CTL, MSC demonstrated approximately 50% suppression. CD8(+) cell expansion could not explain the suppressive effects of MSC. Soluble factors produced by MSC were responsible for the retention of 50% CTL responses. Cytokine microarray analyses, noncontact cultures, and functional assays identified a role for IFN-gamma. MSC were identified as the relevant source of IFN-gamma. CONCLUSION: The results show a facilitating role of IFN-gamma on CTL responses, although paradoxical in light of the veto properties of MSC. This report shows that in cases where MSC are used in transplantation for repair of damaged tissue, they can exert an additional role by protecting the host to viral challenges and thereby protect from its immunosuppressive properties.

Neurokinin receptors: relevance to the emerging immune system.

The adult bone marrow (BM )is the major site of the emerging immune system. Hematopoiesis is the process whereby immune cells are generated from a finite number of hematopoietic stem cells. Hematopoiesis is regulated by soluble mediators and inter cellular interactions. A major regulatory mechanism of hematopoiesis involves bidirectional crosstalk with the neural system. This communication mainly occurs by the release of neurotransmitters from innervated fibers. The neurotransmitters interact with specific receptors on BM resident cells and release other hematopoietic regulators such as cytokines. Together, the neurotransmitters and cytokines form a complex network to regulate hematopoiesis. Among BM resident cells, the stromal cells are particularly relevant for two reasons:1) they represent non-neural sources of neurotransmitters, and 2) stromal cells express specific receptors for neurotransmitters. This review focuses on the hematopoietic effects of neurotransmitters belonging to the tachykinins. The two major tachykinins focused in this review are substance P and neurokinin (NK)-A,11 and 10 amino acid peptides. In BM, the tachykinins interact with two major NK receptors:NK-1 and NK-2. These two receptors appear to limit tachykinin-mediated effects on hematopoiesis. The central roles of NK receptors within a network comprising of cytokines and tachykinins are reviewed.