PSGL-1 and generation of tolerogenic dendritic cells

Madrid, Spain -

The advancement of allogeneic stem cell research into the clinic has always been dependent on immunology. In other words, allogeneic stem cell therapy is dependent on ability of the clinician to manipulate the recipient immune system so that the allogeneic cells do not get rejected (host versus graft), nor that the recipient gets attacked by the cells administered (graft versus host).

Immunological tolerance is an active process by which allogeneic tissue is accepted by a recipient without dependence on immune suppressive drugs. This concept of tolerance has been the "Holy Grail" of immunologists ever since Burnet and Medawar won a Noble Prize for it more than half a century ago.

Key cellular players in the process of tolerance are the "tolerogenic dendritic cells", which are immature dendritic cells, or dendritic cells that suppress immunity, as well as the "regulatory T cells". Accordingly, understanding the biology of these two populations is a very important step in immunologists getting closer to the "Holy Grail of Tolerance Induction".

In a recent paper (Urzainqui et al. Functional role of p-selectin glycoprotein ligand 1/p-selectin interaction in the generation of tolerogenic dendritic cells. J Immunol. 2007 Dec 1;179(11):7457-65.) one small step towards understanding tolerogenic dendritic cells was made.

The researchers found that if one crosslinks the molecule P-selectin glycoprotein ligand 1 (PSGL-1) on dendritic cells, the dendritic cells become tolerogenic dendritic cells. The tolerogenic dendritic cells generated expressed immune inhibitory proteins such as the tryptophan degrading enzyme IDO, TGF-beta, and IL-10. Additionally, the tolerogenic dendritic cells were also capable of stimulating generation of T regulatory cells expressing the CD4+ CD25+ FoxP3+ phenotype. Furthermore T regulatory cells generated where capable of functially suppressing activated T cells. In order to demonstrate conclusively that PSGL-1 is involved in generation of suppressive, or tolerogenic dendritic cells, the researchers investigated dendritic cells obtained from PSGL-1 knockout animals. These dendritic cells were more immune stimulatory as compared to dendritic cells from wild-type animals.

The physiological implications of this finding are still unclear. PSGL-1 is usually found on myeloid cells and binds to P-selectin on endothelium. This interactions is involved in the "rolling" phase of leukocyte-stem cell extravasation.

Vaguely I recall some work many years ago about mononcytes naturally transforming to dendritic cells when they cross the endothelium??? maybe this finding is someone related?