How do T cells mediate central nervous system inflammation?

In the history of experimental multiple sclerosis (MS) research, the real breakthrough came around 1970, when experimental autoimmune encephalomyelitis (EAE), a classical animal model of MS, was successfully reproduced in syngeneic rodents, which were transferred with sensitized T cells. In contrast, EAE transfer by immune serum failed without exception. Along with the development of basic immunology and of supportive technology, T cell lines and clones reactive to myelin antigen were established in vitro, and the works using these cloned T cells soon gained popularity and flourished in the research community. Currently, the T cells used for EAE transfer are not derived from the in vitro-generated T cell clones, but are from T cell receptor transgenic mice lymphocytes. However, characterization of pathogenic T cells has stayed in the mainstream of EAE/MS research for almost three decades. The basic research of CD4+ T cells, recognizing myelin peptide associated with major histocompatibility complex class II molecules, actually brought us a deeper understanding of central nervous system inflammation and led us to design a reasonable strategy to combat MS. In fact, most current MS drugs, including fligolimod and anti-Va4 integrin antibody natalizumab, were tested in EAE for their efficacy, and showed efficacy by influencing the functions or behavior of autoreactive T cells in vivo. Although potential target molecules in MS are not restricted to those expressed by T cells, but extend to B cell markers and others, it is still believed that basic research of T cell biology will continuously give us correct answers to key questions and provide us new ideas on how to discover a cure for MS. In this special issue of Clinical and Experimental Neuroimmunology, five review articles were contributed by experts, given the theme entitled “New mechanistic insights into the pathogenesis of multiple sclerosis – from a T cell point of view”. As known to senior scientists over the age of 40 years, the classical paradigm of Th1/Th2 balance prevailed for several years, until Th17 cells were discovered approximately one decade ago. Reflecting the shorter history of research, there remain many questions about the biology of Th17 cells regarding their identity and plasticity. Furthermore, the presence of Th17 cells in the lesions of MS is still a matter of controversy, as reviewed by Thomas Korn, although the clinical relevance of Th17 pathogenic T cells in neuromyelitis optica (NMO) has substantial support. However, elevation of interleukin-17 mRNA was shown in lesions of MS, and Th17 cellassociated molecule, NR4A2, was also increased in the peripheral blood of MS patients, showing the role of Th17 cells in MS. Therefore, Th17-associated molecules, NR4A2 and Tob1, are potential targets of therapy in MS and NMO. For future perspectives, the authors and the Editor recognize that more research is required into human T cells in conditions of health and disease. It will be important to re-analyze the human T cell populations without holding any prevailing dogma. Supporting this, CCR2CCR5 Th1 cells, which have not been given attention, unexpectedly increased in the cerebrospinal fluid of patients with MS in relapse, and showed pathogenic potentials. Readers of this special issue might share the opinion with us that application of new technologies will bring the next breakthrough within years, and immunology textbooks could require major revision.