The role of costimulation in autoimmune demyelination

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated, autoimm une disorder characterized by central nervous system (CNS) inflammation and demyelination, features reminiscent of the human disease, multiple scleros is (MS). In addition to the signal the encephalitogenic T cell receives thr ough the T cell receptor (TCR), a second signal, termed costimulation, is r equired for complete T cell activation. The B7 family of cell surface molec ules expressed on antigen presenting cells (APC) is capable of providing th is second signal to T cells via two receptors, CD28 and CTLA-4. Our studies have shown that costimulation provided by B7 molecules to its ligand CD28 is important in the initiation of the autoimmune response in EAE. Further, it appears the costimulation provided by B7-1 is important in disease devel opment, while B7-2 may play an important regulatory role. We and others lat er showed that B7/CTLA-4 interaction plays a critical role in down-regulati ng the immune response. Previous work has shown that activated T cells and T cells of a memory phenotype are less dependent on costimulation than naiv e T cells. T cells reactive with myelin components that are involved in the pathogenesis of EAE and possibly MS would be expected to have been activat ed as part of the disease process. Building upon our prior work in the EAE model, we have tested the hypothesis that myelin-reactive T cells, which ar e relevant to the pathogenesis of CNS inflammatory demyelination, can be di stinguished from naive myelin-reactive T cells by a lack of dependence upon costimulation for activation and that the costimulatory requirements of th ese myelin-reactive T cells change during the course of disease. Our studie s in the EAE model have also addressed the mechanisms of extrathymic (perip heral) T cell tolerance following intravenous (i.v.) administration of high dose antigen. It is believed that TCR signaling in the absence of costimul ation is a vital component of peripheral tolerance mechanisms. However, rec ent evidence suggests that peripheral tolerance of antigen-specific T cells induced in vivo may require CTLA-4 engagement of the tolerized T cells. We have begun to examine the molecular mechanisms of tolerance induction foll owing intravenous and intraperitoneal administration of myelin antigens in the EAE model and test the hypothesis that tolerance induction is dependent on the B7:CD28/CTLA-4 pathway. The results from our studies will enhance o ur understanding of the role that myelin-reactive T cells may play in the p athogenesis of MS. We have determined that MBP-reactive T cells in MS patie nts an less dependent upon CD28 costimulation than in normal controls. sugg esting that these T cells were previously primed in vivo. Characterization of these CD28-independent myelin-specific T cells will have broad implicati ons for a variety of immunologically based therapies in diseases such as MS . (C) 2000 Elsevier Science B.V. All rights reserved.