Serial analysis of gene expression provides new insights into regulatory T cells

It is now possible to induce donor-specific transplantation tolerance in adult rodents using a number of therapeutic strategies. Such peripheral tolerance is maintained by regulatory CD4+ T cells, not only in transplantation models, but also in autoimmunity. Differential gene expression analyses have been used to identify potential new markers for regulatory T cells, aiming to reveal new insights into their mechanisms of action, and to find novel targets for therapeutic manipulation of the immune system.     

Remembrance of things past

The semantic differential was used to value five earliest memories and five events anticipated in the future of 51 male and 37 female college students. It was expected, based on personality theories, that there would be a significant relationship between perceptions of early memories and future events. The results with this population revealed highly significant differences (t = 10.51). Possible explanations for the unexpected findings were presented.     

Cardiac memory … new insights into molecular mechanisms

'Cardiac memory' describes an electrocardiographic T wave vector change, recorded during normal sinus rhythm that reflects the QRS complex vector during prior periods of ventricular pacing or arrhythmia. In this brief review we consider the mechanisms responsible for cardiac memory, which offer a unique window for relating molecular determinants of repolarization to their expression in the function of ion channels and in the electrophysiology of the heart. Understanding the steps that translate the molecular mechanisms for memory into clinical expression in this relatively straightforward model facilitates our comprehension of the complex pathways that order normal cardiac repolarization and repolarization changes.     

In remembrance of things past: memory T cells and transplant rejection

Summary:  A cardinal feature of the adaptive immune response is its ability to generate long-lived populations of memory T lymphocytes. Memory T cells are specific to the antigen encountered during the primary immune response and react rapidly and vigorously upon re-encounter with the same antigen. Memory T cells that recognize microbial antigens provide the organism with long-lasting protection against potentially fatal infections. On the other hand, memory T cells that recognize donor alloantigens can jeopardize the survival of life-saving organ transplants. We review here the immunobiology of memory T cells and describe their role in the rejection of solid organ allografts.     

Unidirectional development of CD8+ central memory T cells into protective Listeria-specific effector memory T cells

Three distinct subsets of antigen-experienced CD8(+) T cells have been identified so far: short-living effector T cells (T(EC)) and two long-living subsets, described as central (T(CM)) and effector memory (T(EM)) T cells. The lineage relationships of these subpopulations as well as their involvement in protection have not yet been conclusively determined. We recently described a novel marker combination (CD127 and CD62L) to identify all three major CD8(+) T cell subsets in mice infected with Listeria monocytogenes (L.m.). Extensive lineage relationship analyses on highly purified subpopulations after in vitro and in vivo stimulation demonstrated that T(CM) can develop into T(EM) or T(EC), whereas T(EM) can only progress to T(EC) cells. Short-living T(EC) never regained a T(EM) or T(CM) phenotype. These data strongly suggest a hierarchical and unidirectional order of developmental stages. In vivo priming protocols that preferentially induced one of the different CD8(+) T cell subsets demonstrated that predominance of T(EM) (CD40 stimulation) correlated best with effective protection against L.m., whereas generation of neither T(CM) (by immunization with heat-killed L.m.) nor T(EC) (by systemic co-administration of CpG during primary infection) conferred substantial long-term protective immunity. These findings have important implications for the design of more effective T cell-based vaccines.     

Burkitt's lymphoma: new insights into molecular pathogenesis

The World Health Organisation classification reports three subcategories of Burkitt's lymphoma (BL)--endemic, non-endemic, and immunodeficiency associated--proposed to reflect the major clinical and genetic subtypes of this disease. These different types of BL have been reviewed and studied by immunohistochemistry and molecular methods. The results point out the heterogeneity of BL and suggest that AIDS related BL may have a different pathogenesis from that of classic BL.     

CD4 memory T cells on trial: immunological memory without a memory T cell

Immunological memory crucially depends on CD4 T cells. In contrast with B cells, we find no decisive evidence that CD4 T cells are permanently altered by antigen stimulation. We propose that the memory response is derived from an increase in frequency of resting na?ve-like CD4 T cells with a half-life of years (or months in rodents), rather than the currently proposed specialized T-cell types that have a known lifespan of days. In addition, residual antigen will significantly influence the longevity of a memory response. Our model offers a new insight into immunological memory that could assist the development of CD4 T cell-based vaccines.     

Childhood asthma: new insights into management.

Recently, a concerted effort has been made to reverse the trend of increasing asthma mortality and morbidity. One additional strategy might be to recognize patients at risk for persistent asthma and to intervene early. This review summarizes new information on asthma pathogenesis that has helped shape a new direction in managing childhood asthma. At the core is the recognition that asthma is a chronic inflammatory disease. Subsequently, inhaled steroids, the most potent anti-inflammatory asthma medications, have emerged as the cornerstone of the management of persistent asthma. The recent report of the National Heart, Lung, and Blood Institute's Childhood Asthma Management Program provides a comprehensive "profile of performance" for 3 treatment choices for the management of persistent asthma. This study answers questions regarding the benefits and shortcomings of the medications evaluated and prompts a closer evaluation of the long-term effects of other treatment strategies, including medications currently being developed. Although intervention with inhaled steroids offers new opportunities to control the development of asthma, one must be cognizant of potential risks in early and long-term therapeutic intervention. This review provides a perspective on our present knowledge, the rationale for early intervention, and opportunities for more aggressive therapy, as well as speculation on how ongoing clinical research will continue to play a role in advancing asthma care and moving toward a "cure" for this life-threatening disease.     

Mesenchymal stem cell therapy induces glucocorticoid synthesis in colonic mucosa and suppresses radiation-activated T cells: new insights into MSC immunomodulation

Non-neoplastic tissues around an abdomino-pelvic tumor can be damaged by the radiotherapy protocol, leading to chronic gastrointestinal complications that affect the quality of life with substantial mortality. Stem cell-based approaches using immunosuppressive bone marrow mesenchymal stem cells (MSCs) are promising cell therapy tools. In a rat model of radiation proctitis, we evidenced that a single MSC injection reduces colonic mucosa damages induced by ionizing radiation with improvement of the re-epithelization process for up to 21 days. Immune cell infiltrate and inflammatory molecule expressions in the colonic mucosa were investigated. We report that MSC therapy specifically reduces T-cell infiltration and proliferation, and increases apoptosis of radiation-activated T cells. We assessed the underlying molecular mechanisms and found that interleukin-10 and regulatory T lymphocytes are not involved in the immunosuppressive process in this model. However, an increased level of corticosterone secretion and HSD11b1 (11β-hydroxysteroid dehydrogenase type 1)-steroidogenic enzyme expression was detected in colonic mucosa 21 days after MSC treatment. Moreover, blocking the glucocorticoid (GC) receptor using the RU486 molecule statistically enhances the allogenic lymphocyte proliferation inhibited by MSCs in vitro and abrogates the mucosal protection induced by MSC treatment in vivo. Using the irradiation model, we found evidence for a new MSC immunosuppressive mechanism involving GCs.     

Single-cell force spectroscopy: mechanical insights into the functional impacts of interactions between antigen-presenting cells and T cells

Antigen recognition and discrimination by T lymphocyte are essential in initiating appropriate immune responses. The mechanisms underlying exquisite sensitivity and specificity of antigen discrimination are not fully elucidated but involved physical intercellular interactions between T cell and antigen-presenting cell (APC). The specificity of T-cell activation is tightly regulated by T-cell receptor (TCR) recognition of antigenic peptides in complex with major histocompatibility complex (pMHC) glycoproteins on the cell surface of APC. Antigen recognition via TCR/pMHC interactions, together with other co-receptors and co-stimulatory molecules, are spatially organized into the two-dimensional contact zone between T cells and APC, resulting in the formation of an immune synapse (IS). Here, we will review current implementations and applications of a cutting-edge biophysical technique, namely single-cell force spectroscopy (SCFS) that allows us to quantify mechanical forces of IS at APC/T cell-cell contact. The functional impacts of the mechanical strength in regulating T-cell functional activity will be discussed. We will also describe limitations of SCFS techniques, and outline recent investigations focusing on the functional roles of IS as mechanotransducer in regulating T-cell activities.     

Fetal cells and cell-free fetal DNA in maternal blood: new insights into pre-eclampsia

The examination of fetal cells, specifically erythroblasts, and cell-free fetal DNA from the blood of pregnant women is currently the subject of intense research with the aim of developing new risk-free methods for prenatal diagnosis. An unexpected finding made during these studies was that the traffic of fetal erythroblasts into the maternal peripheral circulation was enhanced in pre-eclampsia. Independent prospective studies examining samples collected in the second trimester indicated that this perturbation in fetal cell trafficking occurs early in pregnancy, well before the onset of pre-eclampsia symptoms. The quantitative analysis of cell-free fetal and maternal DNA levels indicated that these concentrations were elevated in a co-ordinate manner in manifest pre-eclampsia, and that these elevations corresponded to disease severity. On the other hand, analysis of prospectively collected samples indicated that only cell-free fetal but not maternal DNA levels were elevated before onset of symptoms in pregnancies which subsequently developed pre-eclampsia. These data support hypotheses suggesting that pre-eclampsia is a multi-step disorder, initiated by a placental lesion that occurs early in pregnancy and which subsequently leads to a systemic maternal inflammatory response and associated endothelial cell damage.     

Tissue-resident memory T cells

Tissues such as the genital tract, skin, and lung act as barriers against invading pathogens. To protect the host, incoming microbes must be quickly and efficiently controlled by the immune system at the portal of entry. Memory is a hallmark of the adaptive immune system, which confers long-term protection and is the basis for efficacious vaccines. While the majority of existing vaccines rely on circulating antibody for protection, struggles to develop antibody-based vaccines against infections such as herpes simplex virus (HSV) and human immunodeficiency virus (HIV) have underscored the need to generate memory T cells for robust antiviral control. The circulating memory T-cell population is generally divided into two subsets: effector memory (T_EM) and central memory (T_CM). These two subsets can be distinguished by their localization, as T_CM home to secondary lymphoid organs and T_EM circulate through non-lymphoid tissues. More recently, studies have identified a third subset, called tissue-resident memory (T_RM) cells, based on its migratory properties. This subset is found in peripheral tissues that require expression of specific chemoattractants and homing receptors for T-cell recruitment and retention, including barrier sites such as the skin and genital tract. In this review, we categorize different tissues in the body based on patterns of memory T-cell migration and tissue residency. This review also describes the rules for T_RM generation and the properties that distinguish them from circulating T_EM and T_CM cells. Finally, based on the failure of recent T-cell-based vaccines to provide optimal protection, we also discuss the potential role of T_RM cells in vaccine design against microbes that invade through the peripheral tissues and highlight new vaccination strategies that take advantage of this newly described memory T-cell subset.     

Nonpolarized memory T cells

Nonpolarized T cells, defined as memory T cells that are deficient in the production of T helper 1 (Th1) or Th2 cytokines, are now receiving overdue attention. Predominantly of a lymphoid-tissue-homing phenotype, they comprise a memory T-cell pool for efficient secondary immune responses, as well as a CXC-chemokine receptor 5 (CXCR5)⁺ T-cell subset specialized to provide help for B cells. Thus, the conventionally overlooked, nonpolarized T-cell population is proving to have diverse activities important to immune function.