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Object: Co-stimulatory molecules are important for cell-cell interactions between immune cells, not only for cell activation, but for suppression. Several new co-stimulatory molecules have recently been discovered, and in this study we used immuno-histological and -cytological methods to investigate the distribution of such molecules in the germinal center of human tonsils., Materials and Methods: Tonsils surgically removed from patients with sleep apnea and habitual tonsillitis were examined. Expression of co-stimulatory molecules in immune cells was investigated immuno-histologically in frozen sections, and immuno-cytologically by flow cytometry., Results: PD-L1 was found to be expressed on both GCDCs (germinal center dendritic cells) and FDCs (follicular dendritic cells). ICOS and PD-1 were expressed on activated CD4 T cells located in the light zone of the germinal centers. 4-1BB was expressed on the FDCs, in human tonsils, but not on activated T cells., Conclusion: GCDCs and FDCs are likely to function not only T cell activation but in negative regulation of T cells through PD-L1 expression. ICOS molecules contributing to positive signals, and PD-1 to negative signals were simultaneously expressed on a subset of activated T cells, suggesting that signal balance between ICOS and PD-1 is important for T-cell fate.

Most of immunopathological knowledge on multiple sclerosis(MS) is from studies based on the hypothesis that MS is a Th1 disease. Understanding differentiation and crossregulation of Th1 and Th2 cells is pivotal to grasp the immunological theories of MS. However, one need be aware that Th1 disease hypothesis may not represent all of MS because effector cells as well as regulatory cells have not been firmly identified. In addition, a few EAE studies and clinical trials suggest that Th1 cytokine could be protective and that Th2 cells could be encephalitogenic although much more studies have supported the hypothesis. Here basic knowledge about helper T cells is first described. And then, the rationale of the Th1 disease hypothesis is discussed.

To clarify the local immune responses in inflammatory myopathies, we examine recent studies on expression of adhesion and costimulatory molecules. Adhesion molecules participate in MNC influx from blood vessels into muscle tissues and interactions of inflamed muscle cells with surrounded MNC. These antigens may work as costimulatory molecules in antigen presenting process by muscle cells, as well as in augmentation of inflammation by infiltrating MNCs.

Optimal T cell activation requires at least two signals. One is provided by the interaction between antigen-specific T cell receptor and antigen-MHC complexes. The other is provided by costimulatory signals. One best characterized costimulation is mediated by CD28/CTLA4-CD80/CD86 (CD28/B7). In the past decade, costimulatory signal mediated by CD28 has been shown to be critical to augment T cell proliferative response and effector function such as cytokine production. Recent intensive analysis of the CD28/B7 pathway have revealed unexpected means in which this pathway may be involved in the maintenance and breakdown of self-tolerance. In vivo studies using antagonists or transgenes of this pathway reveals that inappropriate expression of CD80, ligand for CD28/CTLA4, could induce autoimmunity and blockade of CD28/B7 pathway could ameliolate several autoimmune disease models. Furthermore, CD80 and CD86 plays differential roles for the development of autoimmune disease since helper T cell development is differentially affected by the blockade of either. CD80 or CD86 in certain conditions. More recent studies demonstrated the crucial role of CTLA4 in negatively regulating T cell activation and autoreactivity. Taken together, this pathway play pivotal roles for autoimmunity, and manipulation of this pathway raises the possibility for controlling autoimmune diseases.