Current perspectives on the role of IL-17 in autoimmune disease

Until recently, autoimmune diseases had been categorized as either Th1- or Th2-mediated diseases. However, the discovery of a novel subset of helper T cells producing interleukin (IL)-17, ie, Th17 cells, changed this paradigm. Currently, IL-17 and Th17 cells are implicated in many autoimmune diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel diseases. Such conclusions were initially drawn from observations in animal models of autoimmune diseases, and accumulating data from clinical research also support the involvement of IL-17 in human diseases as well. Reagents targeting Th17-related molecules have been under clinical investigation for some diseases but have not always been effective in controlling disease activity. Consistent with this, it has become evident that there are substantial differences in the development of Th17 cells and in the way they function in autoimmune diseases between humans and experimental animals. Thus, further investigation is needed before we can draw any conclusions about the importance of IL-17 and Th17 cells in human autoimmune diseases

Development of a new mAb specific to mouse Vγ6 chain

There are seven Vγ gene segments in the TCR γ chain loci of mice. We developed monoclonal antibodies (mAbs) specific to the Vγ6 chain (Heilig & Tonegawa nomenclature). By immunizing Vγ4/6 KO mice with complementarity-determining region peptides in Vγ6 chains, we generated three hybridomas. These hybridomas produced mAbs capable of cell surface staining of Vγ6/Vδ1 gene–transfected T-cell line lacking TCR as well as of Vγ1− Vγ4− Vγ5− Vγ7− γδ T cells and the CD3high TCRδint γδ T cells in various organs. The location of Vγ6+ γδ T cells, which peaked in the newborn thymus, was associated with mTEC. In vivo administration of clone 1C10-1F7 mAb impaired protection against Klebsiella pneumoniae infection but ameliorated psoriasis-like dermatitis induced by imiquimod treatment. These new mAbs are useful to elucidate the development, location, and functions of Vγ6 γδ T cells in mice

The Search for the Pathogenic T Cells in the Joint of Rheumatoid Arthritis: Which T-Cell Subset Drives Autoimmune Inflammation?

Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting systemic synovial tissues, leading to the destruction of multiple joints. Its etiology is still unknown, but T-cell-mediated autoimmunity has been thought to play critical roles, which is supported by experimental as well as clinical observations. Therefore, efforts have been made to elucidate the functions and antigen specificity of pathogenic autoreactive T cells, which could be a therapeutic target for disease treatment. Historically, T-helper (Th)1 and Th17 cells are hypothesized to be pathogenic T cells in RA joints; however, lines of evidence do not fully support this hypothesis, showing polyfunctionality of the T cells. Recent progress in single-cell analysis technology has led to the discovery of a novel helper T-cell subset, peripheral helper T cells, and attracted attention to the previously unappreciated T-cell subsets, such as cytotoxic CD4 and CD8 T cells, in RA joints. It also enables a comprehensive view of T-cell clonality and function. Furthermore, the antigen specificity of the expanded T-cell clones can be determined. Despite such progress, which T-cell subset drives inflammation is yet known

The molecular pathogenesis of collagen-induced arthritis in mice--a model for rheumatoid arthritis.

The most widely used model for rheumatoid arthritis is the collagen-induced arthritis (CIA) in mice. This model has gained acceptance since it is reproducible, well defined and has proven useful for development of new therapies for rheumatoid arthritis, as exemplified by the most recent advancement using TNFalpha neutralization treatment. The collagen-induced arthritis model, however, represents only certain pathways leading to arthritis and there is no consensus on how they operate. Nevertheless, we are beginning to understand the immune recognition structures, such as MHC molecules, lymphocyte receptors and type II collagen epitopes, which are of crucial importance for the development of this disease. These provide useful tools for further investigations of the pathogenesis of CIA as well as for understanding the pathogenesis of rheumatoid arthritis

CD5−NK1.1+ γδ T Cells that Develop in a Bcl11b-Independent Manner Participate in Early Protection against Infection

Summary: We recently found that a unique subset of innate-like γδ T cells develops from the DN2a stage of the fetal thymus independently of the zinc-finger transcription factor B cell leukemia/lymphoma 11b (Bcl11b). Herein, we characterize these Bcl11b-independent γδ T cells in the periphery as CD5−NK1.1+ and Granzyme B+, and we show that they are capable of producing interferon (IFN)-γ upon T cell receptor stimulation without Ca2+ influx. In wild-type mice, these cells were sparse in lymphoid tissues but abundant in non-lymphoid tissues, such as the liver. Bcl11b-independent CD5−NK1.1+ γδ T cells appeared and contributed to early protection before Bcl11b-dependent CD5+NK1.1− γδ T cells following Listeria monocytogenes infection, resembling their sequential appearance during development in the thymus. : Bcl11b is essential for transition from the DN2a to the DN2b stage in the thymus. Hatano et al. find that CD5−NK1.1+ γδ T cells develop from the DN2a stage in a Bcl11b-independent manner and participate in host defense at an early stage after bacterial infection in periphery. Keywords: innate immunity, γδ T cell, Bcl11b, DN2a, IFN-γ, Granzyme, IL-17A, host defense, bacteria, Listeria monocytogene