The common gamma chain (gammac) is the central signaling unit for a number of cytokine receptors collectively known as the gammac cytokine receptor family. gammac is critical for ligand binding and signaling by gammac cytokines. gammac cytokine signaling had been thought to be mainly regulated by cytokine-specific receptor alpha chain expression levels with little or no effect by gammac surface levels because gammac expression was presumed to remain unchanged during T-cell activation and development. The extent of gammac cytokine responses is thought to be regulated by cytokine specific receptor subunits and not by the gammac receptor. In contrast to this prevailing view, we have recently reported that gammac itself actively regulates gammac cytokine responses. Interestingly, gammac exerted its regulatory effects not only as a conventional membrane receptor protein but also as a secreted protein whose expression was upregulated upon T-cell stimulation. Here we will review how a soluble form of gammac, which is generated by alternative splicing, regulates gammac cytokine signaling and plays a role in controlling immune activation related to autoimmune disease.
Alternative Splicing ; Autoimmune Diseases* ; Cytokines ; Humans ; Membranes ; Receptors, Cytokine ; T-Lymphocytes

Interleukin-7 (IL-7) is an essential cytokine for T cells. However, IL-7 is not produced by T cells themselves such that T cells are dependent on extrinsic IL-7. In fact, in the absence of IL-7, T cell development in the thymus as well as survival of naive T cells in the periphery is severely impaired. Furthermore, modulating IL-7 availability in vivo either by genetic means or other experimental approaches determines the size, composition and function of the T cell pool. Consequently, understanding IL-7 expression is critical for understanding T cell immunity. Until most recently, however, the spatiotemporal expression of in vivo IL-7 has remained obscured. Shortage of such information was partly due to scarce expression of IL-7 itself but mainly due to the lack of adequate reagents to monitor IL-7 expression in vivo. This situation dramatically changed with a recent rush of four independent studies that describe the generation and characterization of IL-7 reporter mice, all utilizing bacterial artificial chromosome transgene technology. The emerging consensus of these studies confirmed thymic stromal cells as the major producers of IL-7 but also identified IL-7 reporter activities in various peripheral tissues including skin, intestine and lymph nodes. Strikingly, developmental and environmental cues actively modulated IL-7 reporter activities in vivo suggesting that IL-7 regulation might be a new mechanism of shaping T cell development and homeostasis. Collectively, the availability of these new tools opens up new venues to assess unanswered questions in IL-7 biology in T cells and beyond.
Animals ; Biology ; Chromosomes, Artificial, Bacterial ; Consensus ; Cues ; Homeostasis ; Indicators and Reagents ; Interleukin-7 ; Intestines ; Lymph Nodes ; Mice ; Organothiophosphorus Compounds ; Skin ; Stromal Cells ; T-Lymphocytes ; Thymus Gland ; Transgenes

Despite the broad rehabilitative potential of aquatic exercises, the relationship between aquatic exercise and the immune system has not been fully elucidated to date. In particular, there are few specific and delicate immunological approaches to the effect of water temperature on immunity. Thus, we examined the effect of water temperature on immunity during aquatic exercise. The animal tumor model was adopted to examine the impact of aquatic exercise at thermoneutral temperature (TT; 29°C) on immunity compared with aquatic exercise at body temperature (BT; 36°C). Tumor-bearing mice were made to swim in TT water or in BT water for 3 wk and immune cells and their functional activity were analyzed using FACS. Tumor growth was significantly suppressed in mice that exercised in TT than in BT water. The tumor control correlated with the increased number of NK (2-fold), γδT cells (2.5-fold), NKT (2.5-fold), and cytotoxic CD8⁺ T cells (1.6-fold), which play a critical role in anti-tumor immune responses. Furthermore, the functional activity was dramatically improved in the TT group, showing enhanced production of IFNγ in CD8⁺ T cells compared with the BT group. This study demonstrates that aquatic exercise in TT water may improve protective immune responses more effectively than in BT water. Although the effects of water temperature on immune function need further verification in humans, this study suggests that water temperature in human hydrotherapy may be important for improving immune function.
Animals ; Body Temperature ; Exercise ; Humans ; Hydrotherapy ; Immune System ; Interferons ; Mice ; T-Lymphocytes ; Water

As a part of our ongoing search for a safe and efficient anti-tumor vaccine, we attempted to determine whether the molecular nature of certain tumor antigens would influence immune responses against tumor cells. As compared with freeze-thawed or formaldehyde-fixed tumor antigens, heat-denatured tumor antigens elicited profound anti-tumor immune responses and greatly inhibited the growth of live tumor cells. The heat-denatured tumor antigens induced a substantial increase in the anti-tumor CTL response in the absence of any adjuvant material. This response appears to be initiated by strong activation of the antigen-presenting cells, which may recognize heat-denatured protein antigens. Upon recognition of the heat-denatured tumor antigens, macrophages and dendritic cells were found to acutely upregulate the expression of co-stimulatory molecules such as B7.2, as well as the secretion of inflammatory cytokines such as IL-12 and TNF-alpha. The results of this study indicate that heat-denatured tumor extracts might elicit protective anti-tumor adaptive immune responses and also raise the possibility that a safe and efficient adjuvant-free tumor vaccine might be developed in conjunction with a dendritic cell-based tumor vaccine.
Adjuvants, Immunologic ; Animals ; Antibodies, Neoplasm/immunology ; Antibody Specificity/immunology ; Antigens, Neoplasm/immunology ; Cancer Vaccines/*immunology ; Cell Line, Tumor ; Cell Proliferation ; Cytokines/biosynthesis ; Cytotoxicity, Immunologic/immunology ; Dendritic Cells/immunology ; *Hot Temperature ; Immunity, Cellular/immunology ; Immunization ; Immunologic Memory/immunology ; Macrophages, Peritoneal/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasms/*immunology/*pathology ; Survival Analysis ; T-Lymphocytes, Cytotoxic/immunology

Invariant natural killer T (iNKT) cells develop in the thymus upon recognition of CD1d expressed on developing thymocytes. Although CD4 and CD8 coreceptors are not directly involved in the interaction between CD1d and the T cell receptors (TCRs) of iNKT cells, a conspicuous lack of CD8+ iNKT cells in mice raised the question of whether CD8+ iNKT cells are excluded due to negative selection during their thymic development, or if there is no lineage commitment for the development of murine CD8+ iNKT cells. To address this question, we analyzed iNKT cell-specific TCR Valpha14+ transgenic mice, where the Valpha14 transgene forces the generation of iNKT cells. This allows detailed study of the iNKT cell repertoire. We were able to identify CD8+ iNKT cells which respond to the NKT cell-specific glycolipid ligand alpha-galactosylceramide. Unlike conventional iNKT cells, CD8+ iNKT cells produce predominantly IFN-gamma but not IL-4 upon antigen stimulation. We also confirmed the presence of CD8+ iNKT cells in wild type mice. Our results suggest that CD8+ NKT cells do exist in mice, although their population size is quite small. Their Th1-skewed phenotype might explain why the population size of this subtype needs to be controlled tightly.
Animals ; CD8-Positive T-Lymphocytes/*immunology/metabolism ; Galactosylceramides/immunology ; Interferon-gamma/immunology ; Interleukin-4/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Natural Killer T-Cells/*immunology/metabolism ; Receptors, Antigen, T-Cell, alpha-beta/*genetics ; Transgenes

In this study, we report the development of a new dual reporter vector system for the analysis of promoter activity. This system employs green fluorescence emitting protein, EGFP, as a reporter, and uses red fluorescence emitting protein, DsRed, as a transfection control in a single vector. The expression of those two proteins can be readily detected via flow cytometry in a single analysis, with no need for any further manipulation after transfection. As this system allows for the simultaneous detection of both the control and reporter proteins in the same cells, only transfected cells which express the control protein, DsRed, can be subjected to promoter activity analysis, via the gating out of all un-transfected cells. This results in a dramatic increase in the promoter activity detection sensitivity. This novel reporter vector system should prove to be a simple and efficient method for the analysis of promoter activity.
Enzyme Multiplied Immunoassay Technique ; Flow Cytometry ; Fluorescence ; Luminescent Proteins ; Proteins ; Transfection

The reformation of medical curriculum induced the reduction of anatomy course schedule especially in contact hours in anatomy laboratory. It has led to the use of more efficient teaching approaches in anatomy laboratory. The purpose of this work provide a detailed analysis of alternating dissections with reciprocal peer teaching in anatomy laboratory. Students were assigned alphabetically, in teams of eight or nine, to each dissecting table. The team was subdivided into two groups, A and B, each group dissected every other session. Students excused from dissection spent their time with team-based learning and self-directed learning. Dissected peer-teaching groups presented structures from the dissection to groups absent during dissection. Practical exam scores of the alternating dissection indicated no significant difference with those of classical dissection of previous year. Subgroup analysis of practical exam scores in alternating dissection was also no significant difference between group A and B. Assessment of question types showed that correction rates of questions in the dissected region was significantly higher on dissection group assignment. There were 9 questions (out of 86) in which there was a significant difference in correction rates between A and B groups. In conclusion, the laboratory paradigm of alternating dissection with reciprocal peer teaching demonstrated an effective method of learning gross anatomy laboratory for first year medical students.
Appointments and Schedules ; Curriculum ; Humans ; Learning ; Methods ; Students, Medical