4.1BB Induces CD34 To Monocyte Differentiation

Singapore -  

There are numerous examples of molecules associated with immune response having regulatory effects on stem cell function, and vice versa.  Immune control of hematopoiesis can be seen in an issued US patent (# 7,332,158) describing that administration of activated peripheral blood mononuclear cells accelerates neutropoiesis.  On the flip side of the coin, it is known that mesenchymal stem cells can control immune reactions, most interesting, acute graft versus host disease, as well as stimulate regeneration of endogenous damaged tissue, as an example in diabetes.

4.1BB, more formally known as CD137, belongs to the TNF receptor family and is an important costimulatory molecule on T cells, primarily CD8 T cells.  For example, when one activates a T cell in vitro and blocks CD137, there is a reduction in proliferation of the T cells but generation of cytotoxic T lymphocytes is not impaired.  In contrast, when CD137 is blocked in vivo, there is a marked inhbition of amplification of cytotoxic T cell generation.  Particularly it appears that CD137 is needed for clonal expansion and survival of the T cytotoxic cells (Cooper et al. 4-1 BB controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity.  European Journal of Immunology 32:521, 2002).

In a recent study (Jiang et al. Induction of proliferation and monocytic differentiation of human CD34 cells by CD137 ligand signalling. Stem Cells June 19 2008), it was found that the CD137-CD137 ligand interaction is also fundamentally important in CD34 hematopoietic stem cell biology.

The authors found that  CD137 is expressed on bone marrow cells, including stromal mesenchymal cells, and that CD137 ligand is found on a subsent of CD34 cells.  Now expression of a costimulatory molecule such as CD137 on mesenchymal stem cells is interesting enough since mesenchymal stem cells have been shown not only to suppress immunity, but in some cases to increase survival of T cells.  What is more interesting that the scientists found was that activation of the CD137 ligand on the CD34 hematopoietic stem cells actually stimulated the proliferation of the CD34 cells.  Proliferation was interesting since it was associated with induction of specific differentiation of the CD34 cells into monocytes and macrophages but not dendritic cells. 

The crosslinking of immunological molecules to induce differentiation is an interesting proposition.  There is even one company called Tristem that actually claims crosslinking of anti-HLA beta chain antibody on monocytes will induce their retrodifferentiation into CD34 cells.

An interesting question would be whether other markers associated with the immune system are found on hematopoietic stem cells and if they can be modified or manipulation to shift hematopoiesis one way or another.  This can be found pretty easily by searching published gene expression data on CD34 hematopoietic stem cells.