Development of effective vaccines for old mice in a tumor model.

Vaccines are often inefficient in old people and old mice. Few studies have focused on testing vaccines in old populations. Here we used DNA tumor antigen vaccines against melanoma and showed that old mice were not protected.

Herpesviruses and autoimmunity.

Herpesvirus infection, in particular EBV infection, has been implicated in several major autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS) and rheumatoid arthritis (RA). Herpesvirus infection has potential roles in both initiating the autoimmune process and exacerbating disease progression. In particular, EBV has a proposed role in initiating the anti-nucleoprotein antibodies that are characteristic of SLE through molecular mimicry.

Mechanisms of immunization against cancer using chimeric antigens.

Successful approaches to tumor immunotherapy must overcome the physiological state of tolerance of the immune system to self-tumor antigens. Immunization with appropriate variants of syngeneic antigens can achieve this. However, improvements in vaccine design are needed for efficient cancer immunotherapy.

Apoptosis of T cells in peripheral blood and cerebrospinal fluid is associated with disease activity of multiple sclerosis.

Apoptotic elimination of pathogenic T cells is considered to be one of regulatory mechanisms in multiple sclerosis (MS). To explore the potential relationship between Fas-mediated apoptosis and the disease course of MS, we examined apoptosis, defined by annexin V (AV) binding, and Fas (CD95) expression in CD4+ and in CD8+ T cells in MS patients by using five-color flow cytometry. The percentage of AV+CD4+CD3+ cells and CD95+AV+CD4+CD3+ cells in peripheral blood and cerebrospinal fluid (CSF) were significantly decreased in active MS patients compared with inactive MS patients.

The activation of memory CD4(+) T cells and CD8(+) T cells in patients with multiple sclerosis.

To reevaluate whether an association exists between the clinical course of multiple sclerosis (MS) and the activation of memory T cells, we investigated the phenotype of T cells in peripheral blood and cerebrospinal fluid (CSF) of patients with MS using five-color flow cytometry. A cross-sectional study with 39 relapsing-remitting MS patients demonstrated that the percentage of CD25(+)CD45RO(+)CD4(+)CD3(+) cells was significantly increased in peripheral blood as well as in CSF of active MS patients compared with inactive MS patients. A longitudinal study with 11 relapsing-remitting MS patients also showed a higher percentage of CD25(+)CD45RO(+)CD4(+)CD3(+) cells in peripheral blood at the phase of exacerbation than during remission.

Antiviral T cell responses: phalanx or multipronged attack?

Around 700 BCE, a new military formation called the phalanx was established in ancient Greece: a tight column of heavy infantry carrying long spears, or pikes, used in a single prong of attack. Later, in the battle of Marathon described by Herodotus, the Greeks learned the advantages of multipronged attacks, a strategy still used in modern warfare. Is the immune system similar in its approach to combatting pathogens or tumors?

Amplification of autoimmune disease by infection.

Reports of infection with certain chronic persistent microbes (herpesviruses or Chlamydiae) in human autoimmune diseases are consistent with the hypothesis that these microbes are reactivated in the setting of immunodeficiency and often target the site of autoimmune inflammation. New experimental animal models demonstrate the principle. A herpesvirus or Chlamydia species can be used to infect mice with induced transient autoimmune diseases.

A mouse herpesvirus induces relapse of experimental autoimmune arthritis by infection of the inflammatory target tissue.

It is not known what is required for successive relapses in autoimmune diseases or evolution to a progressive chronic disease. Autoimmune arthritis caused by passive transfer of autoantibodies against glucose 6-phosphate isomerase is transient and therefore lends itself well to test for what might extend the disease. Herpesviruses have long been suspected of contributing to human autoimmune disease.

Genomic absence of the gene encoding T cell receptor Vbeta7.2 is linked to the presence of autoantibodies in Sjögren's syndrome.

Objective: It is not yet known whether the absence of certain T cell receptor V(beta) (TCRBV) genes (e.g., due to genomic deletion) has functional significance.

Oligoclonal expansions of antigen-specific CD8+ T cells in aged mice.

Oligoclonal T cell expansions (TCE) are common in old humans and mice. It is not known whether an Ag-specific response becomes more oligoclonal with age, and, if so, how this might alter biological responses or compromise the immune response, thus contributing to the immunodeficiency of aging. We used a tumor antigen response to study these questions.

Staphylococcus aureus express unique superantigens depending on the tissue source.

A comprehensive analysis of Staphylococcus aureus superantigen (SAG) genes was undertaken in isolates from a major hospital and compared with isolates from patients with toxic shock syndrome (TSS). Polymerase chain reaction (PCR) analysis included recently discovered SAGs. Staphylococcal enterotoxin (SE) G and SEI were uniquely expressed in genital isolates.

Tumor antigen drives a persistent oligoclonal expansion of CD8+ T cells in aged mice.

Oligoclonal T cell expansions (TCE) are common in old humans and mice, but it is not known whether the T cell response to a specific antigen is more restricted in old vs. young animals. Herein, we describe an enhanced and prolonged response of tumor antigen-specific CD8 cells in old mice identified by K(d)/peptide tetramers and Vbeta10 staining.

Lack of muco-cutaneous signs of toxic shock syndrome when T cells are absent: S. aureus shock in immunodeficient adults with multiple myeloma.

Staphylococcal toxic shock syndrome (TSS) is an acute life threatening disease. The diagnosis can be made clinically based on diagnostic criteria. The clinical manifestations are caused in large part by there lease of high levels of T-cell-derived cytokines as a result of potent toxins, also called superantigens (SAg), produced by Staphylococcus aureus, but it is not clear which clinical symptoms/signs are strictly T-cell dependent.

Sleeping with the enemy--endogenous superantigens in humans.

We usually think of superantigens (SAg) as dangerous toxins that may cause toxic shock syndrome and death. Now, based on two papers in this issue of Immunity, it seems that we all have SAg genes within us, lying dormant and waiting to be activated under special circumstances.

Productive infection of double-negative T cells with HIV in vivo.

HIV induces CD4 down-regulation from the surface of infected cells by several independent mechanisms, suggesting an important biological role for this phenomenon. In vitro CD4 down-regulation generates T cells with a double-negative (DN) CD4(-)CD8(-) T cell receptor-alphabeta(+) phenotype. However, evidence that this down-regulation occurs in vivo in HIV-infected subjects is lacking, and viral load or viral production assays invariably focus on CD4(+) T cells.

Superantigens in human disease.

Superantigens have been implicated in a wide variety of human diseases. Yet, solid evidence for their role in pathogenesis is available only for Toxic Shock Syndrome and a few other conditions. This evidence is critically reviewed herein.

EBV gene expression not altered in rheumatoid synovia despite the presence of EBV antigen-specific T cell clones.

T cells infiltrating the rheumatoid arthritis (RA) joint are oligoclonal, implicating an Ag-driven process, but the putative joint-specific Ags remain elusive. Here we examine expression of selected EBV genes in RA synovia and find no abnormal expression in RA. DNA of CMV and EBV was detectable by PCR in the synovial tissue of RA.

Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28- cytotoxic effector clones.

CD8 T cells contain a distinct subset of CD8+ CD28- cells. These cells are not present at birth and their frequency increases with age. They frequently contain expanded clones using various TCRalphabeta receptors and these clones can represent >50% of all CD8 cells, specially in old subjects or patients with chronic viral infections such as HIV-1.

Altered expression of CD4, CD54, CD62L, and CCR5 in primary lymphocytes productively infected with the human immunodeficiency virus.

Infection of T cells with HIV-1 induces loss of CD4 and HLA class I from the cell surface. In the present article we have investigated whether changes in expression of other cell surface molecules could be related to HIV infection. To detect HIV-infected cells at the single-cell level, peripheral blood lymphocytes were infected in vitro with HIV-HSA, a reporter virus encoding the murine heat-stable antigen.

Interactions between peripheral blood CD8 T lymphocytes and intestinal epithelial cells (iEC).

Intestinal intraepithelial lymphocytes (iIEL) are primarily CD8 cells and most of them have a CD28- phenotype, the phenotype of effector cytotoxic T cells. We asked whether the predominance of CD8+CD28- T cells in the gut may result from peripheral blood T cells preferentially migrating to the iIEL compartment and adhering to iEC. Compared with CD4 cells, adhesion of resting CD8+ T cells to iEC cell lines was significantly higher.

Mycoplasma superantigen is a CDR3-dependent ligand for the T cell antigen receptor.

Superantigens are defined as proteins that activate a large number of T cells through interaction with the Vbeta region of the T cell antigen receptor (TCR). Here we demonstrate that the superantigen produced by Mycoplasma arthritidis (MAM), unlike six bacterial superantigens tested, interacts not only with the Vbeta region but also with the CDR3 (third complementarity-determining region) of TCR-beta. Although MAM shares typical features with other superantigens, direct interaction with CDR3-beta is a feature of nominal peptide antigens situated in the antigen groove of major histocompatibility complex (MHC) molecules rather than superantigens.

Highly biased CDR3 usage in restricted sets of beta chain variable regions during viral superantigen 9 response.

Superantigens encoded by the mouse mammary tumor virus can stimulate a large proportion of T cells through interaction with germline-encoded regions of the T cell receptor beta chain like the hypervariable region 4 (HV4) loop. However, several lines of evidence suggest that somatically generated determinants in the CDR3 region might influence superantigen responses. We stimulated T cells from donors differing at the BV6S7 allele with vSAG9 to assess the nature and structure of the T cell receptor in amplified T cells and to evaluate the contribution of non-HV4 elements in vSAG recognition.

Expanded CD4+ and CD8+ T cell clones in elderly humans.

The diversity of the human TCR repertoire in aging has been studied by examining the profiles of complementarity-determining region 3 (CDR3) sizes expressed by the BV families. The TCRBV CDR3 profile, which shows size heterogeneity in young adult humans, is significantly restricted in aged humans. Clonal T cell expansions were identified using a PCR-based approach, in one or more BV families from all 14 healthy persons over the age of 65 that we studied.

The endothelial cell ecto-ADPase responsible for inhibition of platelet function is CD39.

We previously demonstrated that when platelets are in motion and in proximity to endothelial cells, they become unresponsive to agonists (Marcus, A.J., L.