T cell tolerance induced by therapeutic antibodies

Abstract

Ever since the discovery of Medawar, over 50 years ago, that immunological tolerance was an acquired phenomenon that could be manipulated in neonatal mice, the ability to induce therapeutic tolerance against autoantigens, allergens and organ grafts has been a major driving force in immunology. Within the last 20 years we have found that a brief treatment with monoclonal antibodies that block certain functional molecules on the surface of the T cell is able to reprogramme the established immune repertoire of the adult mouse, allowing indefinite acceptance of allografts or effective curing of autoimmune diseases. We are only now just beginning to define many of the regulatory mechanisms that induce and maintain the tolerant state with the aim of being able to safely and reliably apply these technologies to human clinical situations.

Figure 1

Different types of regulatory T cells. The four panels depict the four main types of regulatory T cells that have been characterized so far on the left of each panel, together with an indication of their interaction with antigen presenting cells (APC) on the right. (a) Natural regulatory T cells (Treg) are CD4⁺CD25⁺foxP3⁺ cells that are associated with TGF-β for their generation and some of their functions. They can down-modulate APC by CTLA4 cross-linking of CD80/86 molecules, the induction of indoleamine dioxygenase (IDO) and the catabolism of tryptophan. Th3 cells that make predominantly TGF-β may be similar to these Treg. (b) Anergic T cells are associated with T cell activation in the absence of costimulation and are hyporesponsive to antigen due to the induction of the E3-ubiquitin ligases GRAIL, Itch and cbl-b that cause degradation of the T cell receptor signalling pathway. Anergic cells may suppress by competing for IL-2 and costimulation. (c) Tr1 cells are dependent on IL-10 for their generation, and some of their suppressive functions. They can also modulate the APC via CTLA4, CD80/86 and IDO. (d) The CD8⁺CD28⁻foxP3⁺ suppressor T cell is also associated with an IL-10 rich environment and is able, at least in the human system, to modulate the dendritic antigen presenting cell to express the molecules ILT3 and ILT4 that present to further T cells to induce anergy and CD4⁺CD25⁺ Treg cells.

Figure 2

Blocking CD4 induces foxP3 and dominant tolerance to grafted tissue. Under normal circumstances a foreign tissue graft will stimulate alloantigen reactive CD4⁺ T cells to generate activated and effector T cells that lead to graft destruction. In the presence of non-depleting, but blocking, monoclonal antibodies to CD4, a proportion of the T cells express the regulatory master gene foxP3 in a TGF-β dependent manner. These foxP3⁺ T cells not only develop the ability to suppress both the activation and differentiation of naïve T cells, but also seem to promote the generation of IL-10 dependent Tr1 cells. The foxP3⁺ and Tr1 cells are both found at the site of the tissue graft and probably act together to maintain robust dominant tolerance of the graft.