Treg cells causing "alternative activation" of monocytes

London, UK -

In immunology, the notion that T cells are activated by antigen presenting cells has been around for decades. At one time, it was believed that T cells are activated by "immune RNA" generated from antigen presenting cells, this immune RNA being able to "instruct" the T cell to go after specific antigens. Afterwards, the major histocompatibility molecules were demonstrated to carry specific peptides and present them to the T cell receptor. The next big advancement in immunology was the discovery that the dendritic cell acts as a "specialized" antigen presenting cell, having thousand-fold more potency at activating T cell responses as compared to other antigen presenting cells such as the monocyte or the B cell.

Dendritic cells were subsequently recognized to have both immune stimulatory and immune suppressive properties. This depends on the type of dendritic cell, the maturation status of the dendritic cells, as well as previous "conditioning" that the dendritic cell has had. For example, dendritic cells that are immature are generally considered to be poor activators of T cells, or in some cases actually preferentially activating Treg cells. While the majority of the immunology community has been focusing on dendritic cells, both for activation and suppression of the immune system, a small group of scientists have been focusing on the monocyte/macrophage. The importance of the monocyte is that they are found at far higher frequency than dendritic cells, and of course can be differentiated under certain conditions into dendritic cells.

The alternatively activate macrophage is characterized by preferential use of arginase instead of iNOS in terms of arginine metabolism, and is associated with a state of immune suppression. Conditions such as cancer are often associated with intratumor alternatively activated macrophages. The alternatively activated macrophage can do certain things that a dendritic cell can not do. For example, dendritic cells do not stimulate angiogenesis, whereas alterantively activated macrophages can.

It is widely known that the dendritic cell is one of the targets of the Treg cell in terms of immune suppression. This was originally demonstrated in elegant experiments by Dr Wei-Ping Min at the university of Western Ontario, who described a self perpetuating feedback loop between Treg and tolerogenic DC which was responsible for the continuation of allograft tolerance.

In a recent paper (Tiemessen et al. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A. 2007 Nov 27) this same concept has now been applied to macrophages. The investigators demonstrated that culturing Treg cells with macrophages led to upregulation of several features of alternative activation, specifically increased expression/production of CD206, CD163, and the chemokine CCL18. In agreement with the potential induction of alternative activation, the co-cultured macrophages started displaying augmented propensity for phagocytosis.

Immunologically, the Treg-generated alternatively activated macrophages appeared to be suppressive based on:

1. Low expression of HLA-DR
2. Reduced inflammatory cytokine production after endotoxin treatment
3 Suppressed NF-kappa B translocation

The investigators demonstrated that the "programming" of macrophages to transform into the alternative activation state was associated with cytokine dependent and independent signals made by the Treg.

This fundamental discovery will set the stage for investigating control of activities such as angiogenesis by Treg cells.

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