Crystallography, X-Ray ; Receptors, Antigen, T-Cell ; chemistry ; immunology ; metabolism ; T-Lymphocytes ; immunology ; metabolism

T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCR-engineered T cells began more than two decades ago, with numerous preclinical studies showing that such cells could mediate tumor lysis and eradication. The success of these trials provided the foundation for clinical trials, including recent clinical successes using TCR-engineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1). These successes demonstrate the potential of this approach to treat cancer. In this review, we provide a perspective on the current and future applications of TCR-engineered T cells for the treatment of cancer. Our summary focuses on TCR activation and both pre-clinical and clinical applications of TCR-engineered T cells. We also discuss how to enhance the function of TCR-engineered T cells and prolong their longevity in the tumor microenvironment.
Animals ; Antigens, Neoplasm ; immunology ; metabolism ; Humans ; Neoplasms ; immunology ; metabolism ; Receptors, Antigen, T-Cell ; genetics ; metabolism ; T-Lymphocytes ; immunology ; metabolism

T cell recognition of foreign peptide antigen and tolerance to self peptides is key to the proper function of the immune system. Usually, in the thymus T cells that recognize self MHC + self peptides are deleted and those with the potential to recognize self MHC + foreign peptides are selected to mature. However there are exceptions to these rules. Autoimmunity and allergy are two of the most common immune diseases that can be related to recognition of self. Many genes work together to lead to autoimmunity. Of those, particular MHC alleles are the most strongly associated, reflecting the key importance of MHC presentation of self peptides in autoimmunity. T cells specific for combinations of self MHC and self peptides may escape thymus deletion, and thus be able to drive autoimmunity, for several reasons: the relevant self peptide may be presented at low abundance in the thymus but at high level in particular peripheral tissues; the relevant self peptide may bind to MHC in an unusual register, not present in the thymus but apparent elsewhere; finally the relevant self peptide may be post translationally modified in a tissue specific fashion. In some types of allergy, the peptide + MHC combination may also be fully derived from self. However the combination in question may be modified by the presence of other ligands, such as small drug molecules or metal ions. Thus these types of allergies may act like the post translationally modified peptides involved some types of autoimmunity.
Animals ; Autoantigens ; immunology ; Autoimmunity ; HLA Antigens ; immunology ; Humans ; Hypersensitivity ; immunology ; Receptors, Antigen, T-Cell ; metabolism ; T-Lymphocytes ; immunology ; metabolism

OBJECTIVETo explore the pathogenesis of rheumatoid arthritis (RA) by studying the expression of T cell receptors (TCRs).

METHODST cell receptor Vbeta (TCR Vbeta) gene usage and expression were analyzed from synovial membrane and peripheral blood of 8 RA patients, 2 osteoarthritis patients and 2 accident amputees. The complementary determining region 3 (CDR3) of 25 TCR Vbeta subfamily genes in unselected T cell populations were amplified semi-quantitatively by reverse transcription-polymerase chain reaction (RT-PCR). The products were further studied by genescan for frequency of Vbeta usage.

RESULTSThe numbers of Vbeta subfamilies expressed by T cells from RA peripheral blood and synovial membrane were not significantly restricted. More importantly, biased Vbeta gene expression in RA synovium was observed and Vbeta6, Vbeta17, and Vbeta22 genes were the predominant subfamilies. It was noteworthy that the expression of Vbeta17 in RA synovium was significantly increased.

CONCLUSIONOur data were consistent with the hypothesis that several antigen or superantigen-driven processes may be involved in the pathogenesis of RA.

Arthritis, Rheumatoid ; genetics ; immunology ; Genes, T-Cell Receptor beta ; Humans ; Synovial Membrane ; metabolism ; T-Lymphocytes ; immunology

CD4(+)CD25(+)CD127(dim/-) regulatory T cells (Tregs) have been implicated in suppressing T cell immune responses to hepatitis B virus (HBV), but the inhibition mechanism has not being clear yet. This study investigated the effects of soluble FGL2 (sFGL2) secreted by Tregs on immune suppression in chronic HBV-infected patients. We verified that sFGL2 protein and mRNA were highly expressed in Tregs. The separated Tregs by using magnetic beads from peripheral blood mononuclear cells (PBMCs) in 20 patients with chronic hepatitis B were co-cultured with PBMCs at a ratio of 1:3 with anti-CD3 stimulating antibody or FGL2 blocking antibody. The proliferation index of CD8(+)T cells after blocking FGL2 was higher than that in blank group (3.58±0.18 vs. 3.28±0.17, P=0.034) in 18 of 20 samples, and lower than that in CD3 stimulation group (3.82±0.19, P=0.026) in 16 of 20 samples. The IFN-γ secreted in the mixed culture in the absence of Tregs was higher than that in the culture in the presence of Tregs, but it could be abolished by FGL2 blocking antibody. These results suggest that sFGL2 protein secreted by Tregs suppresses the proliferation and function of CD8(+) T cells in chronic hepatitis B.
CD8-Positive T-Lymphocytes ; immunology ; metabolism ; Cells, Cultured ; Fibrinogen ; immunology ; metabolism ; Hepatitis B, Chronic ; immunology ; metabolism ; Humans ; T-Lymphocytes, Regulatory ; immunology ; metabolism

UNLABELLEDTo investigate the effect of immune response mediated by the T cells stimulated with the specific antigen (oxidized low-density lipoprotein, oxLDL) on plaque stability in coronary heart disease.

METHODSThis study involved 20 patients with acute myocardial infarction (AMI), 34 with unstable angina pectoris (UAP), 27 with stable angina pectoris (SAP) and 22 healthy control subjects. With MTS/PMS colorimetric assay, the T cells from all the subjects were tested for proliferative response to stimulation by 5 microg/ml oxLDL and 5 microg/ml low-density lipoprotein (LDL). Interferon-gamma (IFN-gamma) concentration in the proliferative response of the T cells was measured with enzyme-linked immunosorbent assay (ELISA).

RESULTSThe proliferative response of the T cells elicited by 5 microg/ml oxLDL stimulation was significantly higher in the AMI and UAP groups than in the SAP and control groups (P<0.05). Similarly, IFN-gamma concentration in the proliferative response of the T cells to 5 microg/ml oxLDL stimulation was significantly higher in the former two groups (P<0.05). In the AMI and UAP groups, 5 microgT cells than 5 microg/ml LDL stimulation (P<0.001).

CONCLUSIONThe immune response mediated by the T cells to specific antigen stimulation, especially the immune response mediated by T helper type 1 (Th1) cells secreting IFN-gamma, may play an important role in the plaque instability and the occurrence of acute coronary syndrome.

Aged ; Coronary Disease ; immunology ; Female ; Humans ; Interferon-gamma ; secretion ; Lipoproteins, LDL ; immunology ; Male ; Middle Aged ; T-Lymphocytes ; immunology ; metabolism ; T-Lymphocytes, Helper-Inducer ; immunology ; metabolism

Animals ; Antigens, CD ; immunology ; Cytokines ; metabolism ; Hepacivirus ; immunology ; Hepatitis C ; immunology ; prevention & control ; virology ; Hepatitis C Antibodies ; biosynthesis ; immunology ; Hepatitis C Antigens ; immunology ; Humans ; Killer Cells, Natural ; immunology ; T-Lymphocytes ; immunology ; metabolism ; T-Lymphocytes, Regulatory ; immunology ; metabolism ; Viral Proteins ; immunology

BACKGROUNDSystemic sclerosis (SSc) is an autoimmune disease that has three major components: inflammation, fibrosis, and vasculopathy. T-helper 17 cell (Th17) and regulatory T cell (Treg) are considered to be critical for autoimmune disease pathogenesis. The role of Th17 and Treg in SSc is still unclear. The aim of this study was to detect the presence of Th17s and CD4(+)CD25(+) Tregs in peripheral blood samples from SSc patients and to investigate the possible roles of these two T cell subsets in SSc pathogenesis.

METHODSTh17s (CD4 and IL-17 positive) and CD4(+)CD25(+) Tregs (CD4, CD25 and Foxp3 positive) in the peripheral blood mononuclear cells of 53 SSc patients and 27 healthy controls were counted by flow cytometry. The differences between SSc and control patients were analyzed. Clinical parameters, including disease duration, duration of the second symptoms, Modified Rodnan Skin Score (MRSS), anti-topoisomerase I antibody, anti-U1 ribonucleoprotein (RNP) antibody, systemic involvements, pulmonary function test (PFT) and high resolution computed tomography (HRCT) score were prospectively collected following EUSTAR (EULAR scleroderma trial and research group) protocols. The correlations between the experimental and clinical data were investigated.

RESULTSThe ratio of Th17 in SSc patients was significantly elevated compared to healthy controls (8.74% vs. 4.41%, P < 0.001). The amount of Th17 was positively correlated with disease duration (R = 0.531, P = 0.013) and duration of the second symptoms (R = 0.505, P = 0.023). The ratio of CD4(+)CD25(+) Treg in SSc patients also significantly differed from the healthy controls (3.04% vs. 2.24%, P = 0.018). Elevated Tregs were more frequently observed in patients with a high interstitial lung disease (ILD) score on computed tomography (24/36) compared with patients with normal ILD scores (4/12, P = 0.043). Elevated Tregs were also more often observed in patients with low carbon monoxide diffusing capacity (DLCO) (24/34) compared with patients with normal DLCO (4/11, P = 0.042).

CONCLUSIONST cell abnormalities are remarkable in systemic sclerosis. Th17s proliferate and their numbers increase with lengthened disease duration. Th17s might participate in both inflammation and fibrosis by secreting IL-17. CD4(+)CD25(+) Tregs also proliferate in SSc and may play important roles in promoting fibrosis.

CD4-Positive T-Lymphocytes ; metabolism ; Cells, Cultured ; Flow Cytometry ; Humans ; Interleukin-2 Receptor alpha Subunit ; metabolism ; Scleroderma, Systemic ; immunology ; metabolism ; T-Lymphocytes, Regulatory ; immunology ; metabolism ; Th17 Cells ; metabolism

BACKGROUND: Asbestos fibers possess tumorigenicity and are thought to cause mesothelioma. We have previously reported that exposure to asbestos fibers causes a reduction in antitumor immunity. Asbestos exposure in the mixed lymphocyte reaction (MLR) showed suppressed induction of cytotoxic T lymphocytes (CTLs), accompanied by a decrease in proliferation of CD8 METHODS: For MLR, human peripheral blood mononuclear cells (PBMCs) were cultured with irradiated allogenic PBMCs upon exposure to chrysotile B asbestos at 5 μg/ml for 7 days. After 2 days of culture, IL-15 was added at 1 ng/ml. After 7 days of MLR, PBMCs were collected and analyzed for phenotypic and functional markers of CD8 RESULTS: IL-15 addition partially reversed the decrease in CD3 CONCLUSION These findings indicate that CTLs induced upon exposure to asbestos possess dysfunctional machinery that can be partly compensated by IL-15 supplementation, and that IL-15 is more effective in the recovery of proliferation and granzyme B levels from asbestos-induced suppression of CTL induction compared with IL-2.
Asbestos/adverse effects* ; CD8-Positive T-Lymphocytes/metabolism* ; Humans ; Interleukin-15/pharmacology* ; Lymphocyte Activation/immunology* ; T-Lymphocytes, Cytotoxic/metabolism*

Aplastic anemia (AA) is an autoimmune disease which take hematopoietic tissue as target cells. T lymphocyte-mediated cellular immune abnormality plays a key role in the pathogenesis of AA. Increase and hyperfunction of Thl lymphocytes are main feature of AA disease. The recent studies indicated that T-bet is Th1 cell-specific transcription factor, is crucial factor for polarization of CD4(+) T lymphocytes to Th1. High expression of T-bet in AA patients is an important link in pathogenesis of AA. In this article, T-bet and its relation with AA, including expression of T-bet in AA patients, the regulation of T-bet on polarization of CD4(+) T lymphocytes are reviewed.
Anemia, Aplastic ; blood ; immunology ; CD4-Positive T-Lymphocytes ; immunology ; metabolism ; Humans ; Lymphocyte Count ; T-Box Domain Proteins ; immunology ; metabolism ; Th1 Cells ; immunology ; metabolism