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Plaque rupture or erosion with subsequent thrombus formation is the principal mechanism underlying the sudden onset of acute coronary syndromes. Plaque inflammation and increased oxidative stress play important roles in the pathogenesis of plaque destabilization. Macrophages, T lymphocytes, and neutrophils are the dominant types of inflammatory cells at human coronary unstable plaques, such as ruptured plaques or eroded plaques. Calcification is a common finding in human atherosclerotic lesions, and arterial calcification is generally classified into calcification within an atherosclerotic plaque, and Mönckeberg's medial calcific sclerosis characterized by calcific deposits within the media of small and medium-sized muscular arteries. It has been reported that a spotty pattern of calcification is associated with coronary unstable ruptured plaques in patients with acute myocardial infarction. Patients undergoing hemodialysis (HD) have a high prevalence of arterial calcification and cardiovascular events. We recently demonstrated that plasma oxidized low density lipoprotein (LDL) levels significantly increased after a single HD session. This HD session-related increase in plasma oxidized LDL levels could contribute to the progression and acceleration of atherosclerosis and arterial calcification, leading to the development of cardiovascular events in HD patients.

Recently, promising clinical outcomes of cancer immunotherapy including administration of an anti PD-1 antibody targeting for T cell reactivation has gained particular attention worldwide. Adoptive cell therapy with tumor infiltrating lymphocytes and TCR/CAR (Chimeric Antigen Receptor) transgenic T cells are also under development. Although it has become clearer that the efficacy of adoptive cell therapy correlate with the quality of infusing T cells, antigen specific T cells in patients with chronic infection and cancer have been exhausted. We have succeeded to generate rejuvenated antigen specific T cells by reprogramming to pluripotency and differentiation. In this article, we introduce fundamentals of this technology and describe its potential for adoptive cell therapy in the future.

Allogeneic Hematopoietic stem cell transplantation (allo-HSCT) is effective for several diseases, including leukemia, solid tumors, and immunodeficiency. However, there are still some intractable diseases that cannot be treated with HSCT alone. We have developed a new HSCT method, allo-HSCT + thymus transplantation (TT) from the same donor, which induces elevated T cell function with mild graft-versus-host disease (GVHD) in comparison to conventional HSCT alone and HSCT + donor lymphocyte infusion (HSCT + DLI). This method leads to improvement of immune function and the ability of engraftment, and is effective for treatment of autoimmune chronic pancreatitis and sialoadenitis in aging, lupus nephritis in hosts with radioresistance, and supralethal irradiation, in which conventional HSCT alone is ineffective. This method may become a valuable form of clinical therapy for intractable diseases.

Immune system is high-dimensional integrated system distributed in the whole body. Many kinds of, total 10(11) of immune cells are regulated by receiving appropriate signals in appropriate places. We have been attempting to understand immune system by revealing spatiotemporal regulation of immune cells at the whole body level by "Visualization of immune response in vivo". Photoconvertible protein, "Kaede"-Tg mice allowed us to monitor cell-replacement and cell-movement in the whole body by marking cells with color of Kaede from green to red with exposure to violet light. It is applicable to small cell number populations in both lymphoid organs and also peripheral tissues under both normal and pathophysiological conditions. By using this system, we have demonstrated novel findings that "Naive CD4(+) T cell recirculation is an active process that they recirculate through lymphoid organs to seek limited niche for interacting with endogenous antigens and upregulate their function." and "Activated regulatory T cells emigrating from cutaneous immune response is responsible for termination of immune reponse." I will introduce these new tools of us and would like to discuss what is needed to understand immune system in the entire body.

Mucosal associated invariant T (MAIT) cells are restricted by a nonpolymorphic MHC-related molecule-1 (MR1), and express an invariant TCRα chain: Vα7.2-Jα33 in humans and Vα19-Jα33 in mice. MAIT cells are selected in the thymus, but, interestingly, MAIT cells require B cells as well as commensal flora for their peripheral expansion. Bourhis et al demonstrated that MAIT cells display antimicrobial capacity. Both human and mouse MAIT cells have been shown to be activated by Escherichia coli-infected antigen presenting cells in an MR1-dependent manner. MAIT cells show a protective role against Mycobacteriu abscessus or E. coli infections in mice. Human MAIT cells are capable of producing IFNγ and IL-17 and are found in Mycobacterium tuberculosis-infected lung tissues. Thus, MAIT cells play an antimicrobial function under these infectious conditions. MAIT cells play a protective role against autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS), whereas they play a pathogenic role in murine models of arthritis. In patients with autoimmune diseases, the frequency of MAIT cells in peripheral blood was significantly reduced. The frequency of MAIT cells reflected the disease activity in MS patients, suggesting the involvement of MAIT cells in the regulation of autoimmune diseases.

The hypothesis of helper T (T(h))1/T(h)2 cytokine balance was often invoked to explain the development of inflammatory diseases, including inflammatory bowel diseases (IBD). Recently, a newly identified class of regulatory T cells (Tregs), which suppress inflammation and helper T(Th)17 cells, which produce Th17 family cytokines has been recognized as an essential subpopulation in the development of almost all kinds of human and animal inflammatory diseases. T cell subsets can act as terminally differentiated lineages, but they have been increasingly noted to demonstrated plasticity, depending on their surrounding such as intestinal microbiota. Th17 cells and Th1 cells coordinate to play a critical role in the formation of inflammatory bowel diseases. We showed Th1 and Th17 cells are competitive in lymphopenic mice, and that their orchestration results in a merged clinical phenotype of the two types of murine colitis. We also showed that Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. Treg cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells. Here we review T cell development including their plasticity and recent advances in the study of such Treg cells and Th17 cells in the pathogenesis of IBD.

Bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption. This restructuring process called "bone remodeling" is important not only for maintaining bone mass and strength, but also for mineral homeostasis. Excessive osteoclast activity leads to pathological bone resorption, as seen in a variety of local or generalized osteopenic conditions such as rheumatoid arthritis, cancer bone metastasis and osteoporosis. The immune and skeletal systems share various molecules including cytokines, signaling molecules, transcription factors and membrane receptors. The scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions, the elucidation of which will provide a scientific basis for future therapeutic approaches to diseases related to the immune and skeletal systems.

The immune system plays a critical role in the pathophysiology of postmenopausal osteoporosis. Estrogen deficiency induces mild increase in production of proinflammatory cytokines, such as IL-1, IL-6, and TNF-alpha, systemically and locally, which promotes osteoclastogenesis in the bone marrow. The most important cytokine in the context of estrogen deficiency-induced bone loss has been shown to be TNF-alpha produced by bone marrow T-lymphocytes that are stimulated through a complex mechanism involving antigen-presenting cells and various cytokines including IL-7, IFN-gamma, and TGF-beta. Proinflammatory cytokines also suppress osteoblastogenesis, while the crosstalk between T-lymphocytes and marrow stromal cells regulates the osteoclastogenic activity of the latter. Counteracting these interactions could be a novel strategy for osteoporosis treatment.

A repertoire of T cells is primarily formed in the thymus through positive and negative selection of developing thymocytes. The medullary region of the thymus provides a microenvironment that is essential for the establishment of self-tolerance via the depletion of self-reactive T cells and the production of regulatory T cells. Within the medullary microenvironment, medullary thymic epithelial cells play a pivotal role in the establishment of self-tolerance, via the promiscuous expression of tissue-restricted self-antigens and the chemokine-mediated attraction of positively selected T cells from the cortex to the medulla. Positive selection also induces the expression of TNF-superfamily cytokines and thereby nurtures the growth and development of medullary thymic epithelial cells. We will review the mechanisms of how the thymus contributes to the development and selection of T cells, with emphasis on the establishment of self-tolerance in the thymic medulla.

Acute coronary syndromes are multifactorial and occur in response to inflammation, plaque rupture and subsequent thrombosis, progressive mechanical obstruction, and dynamic obstruction. Among potential biomarkers, much interest has focused on biomarkers of inflammation. The process that leads to eventual plaque erosion or rupture involves a number of inflammatory mechanisms, including endothelial dysfunction, leukocyte migration, extracellular matrix degradation, and platelet activation. We discuss herein blood levels of adhesion molecules, matrix metalloproteases, monocyte chemoattractant protein-1, and tissue factor and interferon-gamma production of circulating T cell in patients with acute coronary syndromes. These biomarkers are associated with not only formation and progression of atherosclerotic plaque but also incidence of coronary event.

Glucocorticoid-induced T-cell apoptosis is supposed to require the change of gene expression. Enhanced expression of proapoptotic gene or inhibited expression of antiapoptotic gene seems to be necessary, although the real target gene remain to be elucidated. Recently, it was reported that extracellular signal-regulated protein kinase (ERK) inhibits glucocorticoid-induced T-cell apoptosis. This finding might provide new tools for overcoming glucocorticoid-resistance.

Chronic obstructive pulmonary disease (COPD) is a chronic airway disorder characterized by obstructive airflow limitation which is not completely reversible with treatment. Inflammatory changes in the peripheral airways, especially those with the diameter less than 2 mm(so called small airway disease) have been speculated to be initial steps of COPD. However, it remains unclear which cytokines/chemokines play an essential role in the pathogenesis of these lesions. Studies with bronchoalveolar lavage demonstrated an increase in neutrophil numbers and the neutrophil chemoattractant interleukin-8. Recent studies demonstrated that T lymphocytes, especially CD8 (+) cells are increased and express a variety of cytokines and chemokines, which are involved in cell infiltration and activation. Studies with gene-engineered animals and anti-cytokine treatment will facilitate better understanding the role of cytokines/chemokines, and eventual novel therapy.

Osteoblasts and osteoclasts produce a variety of cytokines to maintain bone homeostasis. One of the most important cytokines, receptor activator of nuclear factor-IkappaB ligand (RANKL), is essential for osteoclastogenesis. Recently, it was shown that activated T cells promote osteoclastogenesis through RANKL expression and also negatively affect osteoclastogenesis through interferon (IFN)-gamma production. Additionally, it was revealed that IFN-beta was involved in osteoclast regulation by signaling cross-talk with RANKL and that it contributed to the maintenance of normal bone mass. These studies indicate that there are complex regulatory interactions between bone-remodeling cells and immune cells, which depend on the balance between RANKL and IFN. Thus, the interaction between T cells and bone cells could be physiologically critical for the maintenance of normal bone metabolism, and IFN might be an attractive cytokine for use in therapy for bone disease in pathological bone resorptive conditions such as rheumatoid arthritis, osteoporosis, osteomyelitis and bone metastasis of cancers.

Central tolerance is established by the repertoire selection of immature T lymphocytes in the thymus, avoiding autoimmune responses to self-antigens. Differential ligand-TCR interactions that result in positive and negative selection initiate differential intracellular signals that, in turn, lead to the survival-or-death decision of immature thymocytes. TCR signal dysregulation due to the mutation of ZAP-70 or defective apoptosis of autoreactive thymocytes due to the deficiency of pro-apoptotic protein Bim impair tolerance and cause autoimmunity. Thymic repertoire selection also induces the development of CD25(+)CD4(+) regulatory T cells, which play important roles for maintaining peripheral tolerance. Furthermore, the establishment of central tolerance requires the development of thymic medulla that is mediated by the activation of NF-kappaB signaling pathway, promiscuous expression of tissue-specific self-antigens by medullary epithelial cells that is regulated by AIRE, and cortex-to-medulla migration of developing thymocytes that is regulated by CCR7-mediated chemokine signals.

Bone destruction in rheumatoid arthritis (RA) is caused by osteoclasts, multinuclear cells of the monocyte/macrophage lineage. Since osteoclast differentiation factor RANKL (receptor activator of NF-kappaB ligand) is expressed on activated T cells and T cells, especially Th1 type cells, are implicated in the pathogenesis of RA, it has been believed that they play an important role in the osteoclastogenesis in RA lesions. However, main Th1-type cytokine IFN-gamma strongly suppresses osteoclastogenesis, casting doubt on the relevancy of Th1 cells as stimulators of osteoclastogenesis. Recently, IL-17 from T cells has been reported to enhance osteoclastogenesis. Characterizing real Th subsets which support osteoclastogenesis would be beneficial to solving a clinically important problem, bone destruction in RA.

Experimental autoimmune encephalomyelitis(EAE), an inflammatory demyelinating disease of the central nervous system(CNS) provoked by myelin antigens, is widely used as a model for multiple sclerosis. Recent studies have shown that apoptosis may contribute to the death of oligodendrocytes and/or neurons, a pathological event leading to neurological deficits. On the other hand, the apoptotic elimination of inflammatory cells such as T cells and macrophages from the CNS is generally believed to contribute to the spontaneous recovery of EAE. Thus, apoptosis is involved in the disease-regulating as well as the disease-promoting processes of EAE.

Pustulosis palmaris et plantaris (PPP) is a pustular skin disease that is closely related to tonsillar focal infection. Patients with this skin disease have shown marked improvements of skin lesions after tonsillectomy. In this study, we evaluated the role of adhesion molecules in the pathogenesis of tonsillarfocal infection related to PPP. The results were that tonsillar lymphocytes of patients with PPP adhered to vessels in the dermis, to vessels running through the dermal papilla, and to vessels in the epidermis at the base of pustules. The adhesion of tonsillar lymphocytes to endothelial cells were significantly blocked by anti-LFA-1 antibody. An immunohistological study revealed that cells infiltrating the dermis expressed LFA-1, whereas ICAM-1, the ligand of LFA-1, was detected on endothelial cells and keratinocytes. It is interesting to note that cells infiltrating the dermis of the erythema stage or the pustule stage of PPP expressed ICAM-1, and the vessels in these stages expressed E-selectin. ICAM-1 was also detected on vessels in the dermis of skin that seemed to be macroscopically normal. These results suggest that tonsillar lymphocytes may have an affinity for the skin of PPP-expressing adhesion molecules such as LFA-1, ICAM-1, and E-selectin. These adhesion molecules seem to be easily activated, not only in skin lesions of PPP, but also in macroscopically normal areas resulting in cellular infiltration and pustule formation.

Nur77 is an orphan member of the steroid receptor superfamily (nuclear receptor). Nur77 family consists of three subtypes and the subtypes show functional redundancy. Nur77 family plays an important role in the apoptotic process of negative selection of T-cells. Moreover, nur77 seems to play a pivotal role in the hypothalamic-pituitary-adrenal axis (HPA axis) during stress response. Nur77 antagonizes the negative feedback effect on the production and secretion of ACTH by glucocorticoid in corticotrope cells of the pituitary gland.

Cytomegalovirus(CMV) infection is associated with several of lymphocyte dysfunction, as well as bone marrow dysfunction, but the precise mechanisms of the dysfunction are still unclear. Splenic T cells of murine CMV (MCMV)-infected mice contained a higher percentage of hypodiploid nuclei and a higher amount of fragmented DNA than those of naive mice, indicating that infection with MCMV induced the apoptotic cell death of T cells. Fas-dependent as well as Fas-independent pathways were suggested to be involved in this induction of apoptosis. Bone marrow cells, especially mature granulocytes in bone marrow, also showed evidence of apoptotic cell death after infection. Involvement of tumor necrotic factor-alpha, but not of Fas, was suggested in the induction of apoptosis of bone marrow cells.

Chronic renal failure (CRF) is often complicated by lymphopenia and sometimes by hepatic dysfunction. To elucidate the involvement of apoptosis in these complications, we analyzed Fas antigen which mediates apoptosis on peripheral blood T cells and hepatic cells. T cells from uremic patients expressed Fas with higher intensity than control T cells. When cultured in vitro, uremic T cells were shown to undergo acceleratd apoptosis in correlation with Fas expression. Immunohistological analysis of liver tissues revealed that hepatocytes in patients both with chronic hepatitis and with CRF expressed higher levels of Fas than those in patients alone with chronic hepatitis. These results suggest that T cells and hepatocytes in CRF may undergo apoptosis by the Fas system.

To clarify the role of apoptosis in the pathogenesis of Sjögren's syndrome (SS), we investigated apoptosis and apoptosis-related molecules in peripheral blood lymphocytes (PBL) and salivary glands (SG) from SS patients and normal controls. In PBL, SS T lymphocytes showed accelerated in vitro apoptosis, and CD4+ T cells showed increased Fas expression compared to those in normal controls. Interestingly, SS T cells also showed increased Bcl-2 expression. The acinar epithelial cells in SS were Fas+ and FasL+, and these cells died by apoptosis. The majority of infiltrating lymphocytes in SS were Fas+ and Bcl-2+, while few lymphocytes expressed FasL. In situ detection of apoptosis showed minimal cell death among lymphocytes, particularly in dense periductal foci. Bax seemed to be expressed in apoptotic acinar cells. In conclusion, blocked apoptosis of SG infiltrating lymphocytes as well as enhanced apoptosis of peripheral T cells may be characteristics of SS. SS acinar cells may die by apoptosis, and this may ultimately lead to SG destruction in SS patients.

Oral tolerance is a phenomenon in which an orally ingested antigen induces systemic hyporesponsiveness to the same antigen. If the mechanism can be applied to autoantigens, it could be a promising mode of antigen-specific immunomodulatory treatment for patients with autoimmune diseases. Multiple ingestion of low doses of antigen induces active suppression. Under this condition, suppression of autoimmune attack to target tissues is mediated by anti-inflammatory cytokines such as TGF-beta, which are released from regulatory T cells triggered antigen-specifically. This type of oral tolerance, termed "bystander suppression", has one advantage of needing to know only the major components of the target tissue instead of exact epitopes of autoimmunity. Utilizing this mechanism, clinical trials of oral tolerance therapy are going on among the patients with multiple sclerosis, rheumatoid arthritis, and uveitis.

Apoptosis is the physiological cell death, and plays an important role in the various fields of immunology, especially (1) in the formation of T cell and B cell repertoires, (2) in the regulation of hyper-activated T and B cells by Fas-FasL, and (3) in the effector phases of eliminating potentially dangerous cells. Although, the exact mechanism of cell death is still unknown, progress has been made in identifying key elements in apoptosis. Particularly, ICE family was found essential for apoptotic execution, and Bcl-2 related proteins can block the molecular events of apoptosis. This article briefly reviewed such "on" and "off" signals in apoptosis, and discussed from the view point that the disturbance of the balance of these signals are relevant to the etiology of autoimmune diseases.

It has been reported that positive selection of natural killer antigen 1.1+ (NK1.1+) T cell antigen receptor (TCR) alpha beta+ thymocytes recently identified among CD4+8- and CD4-8- subpopulations is attributable to major histocompatibility complex (MHC) class Ib ligands expressed on bone marrow (BM) derived components in the thymus. This selection pattern is quite different from NK1.1-T cells of main stream. In the present study, we investigated generation of NK1.1+ TCR alpha beta+ cells in the thymus of aly/aly mouse which lacks lymph nodes and Peyer's patches and shows abnormalities of thymic and splenic structure. We found that the proportion of the NK1.1+ TCR alpha beta+ thymocytes was extremely low in these mice as compared with aly/aly+ and normal C57BL/6 mice. Thymic reconstitution by BM cells from aly/aly+ mice which possess a normal population of NK1.1+ TCR alpha beta+ thymocytes did not restore the NK1.1+ TCR alpha beta+ cell population in the thymus of lethally irradiated aly/aly mouse. When deoxy-guanosine (dGuo)-treated fetal thymi from (B6 x B10.G) F1 mice were transplanted to aly/aly mice which had been thymectomized and reconstituted with BM cells of aly/aly mice, normal proportions of the NK1.1+ TCR alpha beta+ thymocytes were observed in the thymus grafts. Furthermore it was demonstrated that NK1.1+ T cells in aly/aly mice were unable to produce efficiently IL-4 upon in vivo stimulation with anti-CD3. These findings demonstrate that the development of NK1.1+ TCR alpha beta+ cells is accomplished under the influence of not only BM derived components but also in intact microenvironment of lymphoid tissues.

It has been shown that cell adhesion molecules, which mediate lymphocyte adhesion have an ability to provide costimulation signals in the cells. One of the representative adhesion molecules on T lymphocytes, b1 integrin is comprised by several subunits sharing a common b1 subunits, CD29, which is defined by monoclonal anti-4B4 antibody. We have demonstrated that b1 integrins function as a cell surface receptor for extracellular matrix (ECM) protein, such as collagen and fibronectin. We also found that fibronectin, ligand of b1 integrin, synergized with anti-CD3 antibody to promote proliferation of CD4 T cell in a serum free culture system, and also induced an independent signal which would be distinct from the CD3/TcR-mediated signal pathway of activation through the induction of an AP-1 transcription factor. Recent studies revealed that there is an accumulation of CD4+CD29+ T cells, memory T cells as well as prominent increase of a variety of inflammatory cytokines in the synovial fluid of patients with rheumatoid arthritis (RA). This suggests that b1 integrins may play an important role for the inflammatory mechanism in RA. Regulation of signal transduction mediated by adhesion molecules on lymphocytes may be the possible effective way for controlling the pathological inflammatory process in RA.