Cellular immunity is an important component of human immune system and plays a crucial role in the fight against tumor cell or invasive pathogens. Researches on cell-based immunotherapy have long been focused on eliciting tumor-specific CD8+ cytotoxic T lymphocytes (CTL) because of their potent killing activity and their ability to reject transplanted organs. However, the resulting treatments have been surprisingly poor at inducing complete tumor rejection, in both the experimental models and clinical trials. The CD4+ T cells has been studied mainly for their role as helpers for CD8+ CTL, even suggesting that the tumor-specific CD4 T regulatory cells could act as suppressors of antitumor responses. Recent studies indicated that CD4+T cells are not a pure cell lineage with single function, but a cell population with complex functions. Moreover CD4+ T cells may not only be helper cells, but also act as potent effector cells or partners with NK cells that can clear a wide variety of tumors. In a word, the antitumor potential of effector CD4+ T cells might have been underestimated. In this article, the classification and differentiation of CD4+ T cells, the function and secreted cytokines of CD4+ T cells, the CD4+ T cells and tumor immune, the tumor-immuno regulatory effects of CD4+ T cells, and clinical researches of CD4+ T cells are reviewed.
CD4-Positive T-Lymphocytes ; classification ; cytology ; immunology ; Cytokines ; metabolism ; Cytotoxicity, Immunologic ; Humans ; Immunity, Cellular

PURPOSE: This study was done to evaluate the effects of psychosocial interventions on cortisol and immune response in adult patients with cancer. METHODS: MEDLINE via PubMed, Cochrane Library CENTRAL, EMBASE, CINAHL and domestic electronic databases were searched. Twenty controlled trials (11 randomized and 9 non-randomized trials) met the inclusion criteria with a total of 862 participants. Methodological quality was assessed using the Cochrane's Risk of Bias for randomized studies and the Risk of Bias Assessment tool for non randomized studies. Data were analyzed using the RevMan 5.2.11 program of Cochrane library. RESULTS: Overall, study quality was moderate to high. The weighted average effect size across studies was -0.32 (95% CI [-0.56, -0.07], p=.010, I2=45%) for cortisol concentration, -0.62 (95%CI [-0.96,-0.29], p<.001, I2=0%) for T lymphocyte (CD3) and -0.45 (95%CI [-0.74, -0.16], p=.003, I2=0%) for Th lymphocyte (CD4) numbers. Psychosocial interventions were not effective for Tc lymphocyte (CD4), NK cell, monocyte, and cytokine response. CONCLUSION: Although these results provide only small evidence of successful immune modulation, they support the conclusion that psychosocial interventions can assist cancer patients in reducing emotional distress and improving immune response.
CD4-Positive T-Lymphocytes/cytology/immunology ; Cytokines/metabolism ; Databases, Factual ; Humans ; Hydrocortisone/*analysis ; Killer Cells, Natural/cytology/immunology ; Monocytes/cytology/immunology ; Neoplasms/metabolism/pathology/*therapy ; Psychotherapy ; T-Lymphocytes/cytology/*immunology

4-1BB, a member of the tumor necrosis factor receptor (TNFR) superfamily, is a major costimulatory receptor that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. The interaction of 4-1BB with 4-1BBL regulates immunity and promotes the survival and expansion of activated T cells. In this study, the expression of 4-1BB and 4-1BBL was examined during regeneration of the murine thymus following acute cyclophosphamide-induced involution. Four-color flow cytometry showed that 4-1BB and 4-1BBL were present in the normal thymus and were preferentially expressed in the regenerating thymus, mainly in CD4+CD8+ double-positive (DP) thymocytes. Furthermore, the CD4loCD8lo, CD4+CD8lo and CD4loCD8+ thymocyte subsets, representing stages of thymocyte differentiation intermediate between DP and single-positive (SP) thymocytes, also expressed 4-1BB and 4-1BBL during thymus regeneration but to a lesser degree. Interestingly, the 4-1BB and 4-1BBL positive cells among the CD4+CD8+ DP thymocytes present during thymus regeneration were TCR(hi) and CD69+ unlike the corresponding controls. Moreover, the 4-1BB and 4-1BBL positive cells among the intermediate subsets present during thymus regeneration also exhibited TCRhi/int and CD69+/int phenotypes, indicating that 4-1BB and 4-1BBL are predominantly expressed by the positively selected population of the CD4+CD8+ DP and the intermediate thymocytes during thymus regeneration. RT-PCR and Western blot analyses confirmed the presence and elevated levels of 4-1BB and 4-1BBL mRNA and protein in thymocytes during thymus regeneration. We also found that the interaction of 4-1BB with 4-1BBL promoted thymocyte adhesion to thymic epithelial cells. Our results suggest that 4-1BB and 4-1BBL participate in T lymphopoiesis associated with positive selection during recovery from acute thymic involution.
4-1BB Ligand/genetics/*metabolism ; Animals ; Antigens, CD137/genetics/*metabolism ; CD4-Positive T-Lymphocytes/cytology/metabolism ; CD8-Positive T-Lymphocytes/cytology/metabolism ; Cell Adhesion ; Cell Differentiation ; Cell Line ; Cells, Cultured ; Cyclophosphamide/pharmacology ; Epithelial Cells/cytology ; Gene Expression Regulation ; Immunosuppressive Agents/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; RNA, Messenger/genetics ; *Regeneration ; T-Lymphocytes/*cytology/metabolism ; Thymus Gland/*cytology/drug effects/*physiology

OBJECTIVETo investigate the efficacy and mechanisms of recombinant adenovirus containing c-FLIPs (cellular FLICE-inhibitory protein short) in inducing antiapoptosis activation of lymphocyte in vitro.

METHODSc-FLIPs gene was cloned from total RNA of lymphocyte with RT-PCR methods, then constructed recombined adenovirus Ad.c-FLIPs by pAdeasy system. H9 cells infected with Ad.c-FLIPs produced antiapoptosis derived from anti-Apo-1 antibody, and those antiapoptosis evaluated with PI stain flow cytometry (FCM) and Hoechst stain.

RESULTSc-FLIPs gene was successfully cloned from lymphocytes and incorporated into recombinant adenovirus Ad.c-FLIPs.After exposure to anti-Apo-1 for 24 h, the apoptosis of H9 cells preconditioned by Ad.c-FLIPs for 24 h as measured by Hochst stain or FCM significantly decreased, compared with non-preconditioned cells, 3.60% +/- 0.21% vs. 48.33% +/- 7.41%, respectively, indicating that Ad.c-FLIPs preconditioning protected H9 cells against apoptosis induced by anti-Apo-1.

CONCLUSIONRecombinant adenovirus Ad.c-FLIPs effectively induced anti-apoptosis activation of lymphocyte.

Adenoviridae ; genetics ; Apoptosis ; physiology ; CASP8 and FADD-Like Apoptosis Regulating Protein ; genetics ; physiology ; CD4-Positive T-Lymphocytes ; cytology ; metabolism ; Cell Line ; Flow Cytometry ; Humans ; Lymphocytes ; cytology ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transfection ; fas Receptor ; analysis

CD4+ T lymphocytes play a major role in regulation of adaptive immunity. Upon activation, naive T cells differentiate into different functional subsets. In addition to the classical Th1 and Th2 cells, several novel effector T cell subsets have been recently identified, including Th17 cells. There has been rapid progress in characterizing the development and function of Th17 cells. Here I summarize and discuss on the genetic controls of their differentiation and emerging evidence on their plasticity. This information may benefit understanding and treating immune diseases.
Animals ; CD4-Positive T-Lymphocytes/cytology/*immunology ; Cell Differentiation ; Cell Lineage ; Cytokines/*genetics ; Epigenesis, Genetic ; Gene Expression Regulation ; Humans ; Interleukin-17/immunology/metabolism ; T-Lymphocytes, Regulatory ; Th1 Cells/immunology ; Th17 Cells/*immunology ; Th2 Cells/immunology ; Transcription Factors/*genetics ; Transcription, Genetic

Cytomegalovirus (CMV) infection is a dangerous complication in patients with chronic graft versus host disease (cGVHD). CMV-specific immunity depends on the activity of T cells. This study was aimed to investigate the effect of CMV pp65 gene modified dendritic cells (DCs) on activation of autologous T cells. Lentivirus system was utilized to introduce the CMV full-length pp65 gene into mouse DCs; CpG-DNA was used to induce mature DCs; flow cytometry and immunofluorescence were used to determine the expression of antigen and IFNgamma in T lymphocytes. The results showed that the DCs were infected with lentivirus at a multiplicity of infection (MOI) of 50 with optimal infectious efficiency of 30%-40%; mature DCs expressing pp65 gene could stimulate autologous naive T cells to express CD69 specifically; mature DCs expressing PP65 could stimulate autologous CD4+ or CD8+ T cells to produce IFNgamma. It is concluded that CMV pp65-modified and CpG-DNA-induced mature DCs can activate CMV-specific T lymphocytes in vitro.
Animals ; Antigens, CD ; genetics ; metabolism ; Antigens, Differentiation, T-Lymphocyte ; genetics ; metabolism ; Antigens, Viral ; immunology ; CD4-Positive T-Lymphocytes ; immunology ; CD8-Positive T-Lymphocytes ; immunology ; CpG Islands ; genetics ; Cytomegalovirus ; immunology ; DNA ; genetics ; Dendritic Cells ; cytology ; immunology ; metabolism ; Humans ; Interferon-gamma ; genetics ; metabolism ; Lectins, C-Type ; Lentivirus ; genetics ; metabolism ; Mice ; Phosphoproteins ; genetics ; metabolism ; Viral Matrix Proteins ; genetics ; metabolism

OBJECTIVETo investigate the effect of tumor necrosis factor-α-induced protein 8 like-2 (TIPE2) on apoptosis of CD4T lymphocytes in a murine model of severe burn injury.

METHODSA total of 140 male mice were randomly allocated into 6 groups. Small RNA interference technique was used to construct a siTIPE2-overexpressing lentivirus, and severe burn injury models were established in the mice. CD4T cells were purified from spleen of the mice, and the expressions of TIPE2, Smad2/Smad3, P-Smad2/P-Smad3 and Bcl-2/Bimprotein in CD4Tregs were detected. The changes in mitochondrial membrane potential and cytochrome C in CD4T cells were detected, and the activities of caspase-3, caspase-8, and caspase-9 were analyzed.

RESULTSDown-regulation of TIPE2 promoted the apoptosis of CD4T lymphocytes in siTIPE2-burn group, in which the protein expressions of P-smad2/P-Smad3 decreased, Bcl-2 expression increased and Bim expression decreased significantly as compared with the other groups (P<0.01 or 0.05). The mitochondrial membrane potential and cytochrome C expression in CD4T cells were down-regulated in siTIPE2-burn group (P<0.05) with a lowered caspase-3 activity compared with TIPE2-burn group (P<0.01) and decreased caspase-8 and caspase-9 compared with the other groups (P<0.05). The apoptosis rate was the highest in TIPE2-burn group, whose Smad2/Smad3 was higher than that in the sham group (P<0.05) and the expression of P-smad2/P-Smad3 significantly increased compared with the other groups (P<0.05). In TIPE2-burn group, the mitochondrial membrane potential in CD4T cells was decreased (P<0.01), the expression of cytochrome C increased markedly (P<0.01), and the activities of caspase-3, caspase-8, and caspase-9 were all obviously higher than those in the other groups (P<0.05).

CONCLUSIONAs an important immunoregulatory molecule, TIPE2 can promote the apoptosis of CD4T lymphocyte in mice with sever burn injury.

Animals ; Apoptosis ; Burns ; immunology ; CD4-Positive T-Lymphocytes ; cytology ; Caspase 3 ; metabolism ; Caspase 8 ; metabolism ; Caspase 9 ; metabolism ; Down-Regulation ; Intracellular Signaling Peptides and Proteins ; metabolism ; Male ; Mice ; Smad2 Protein ; metabolism ; Smad3 Protein ; metabolism ; Spleen

Blockade of signal 1 or 2 for T-cell activation by the use of anti-CD45RB and anti-CD154 monoclonal antibodies (mAb) (two-signal blockade) has been proven effective in preventing or delaying graft rejection. However, the mechanisms of its immunomodulatory effects are clearly unknown and the present studies were performed to determine how the two-signal blockade modulate allogeneic immune responses, especially T-cell mediated cellular immunity, in a murine skin allograft model. We now report on the profound inhibition of alloreactive T cells by two-signal blockade via CD4-dependent mechanisms. C57BL/6 mice of BALB/c skin allograft were treated with anti-CD45RB, anti-CD154, CTLA4-Ig, or their combinations. For depletion of CD4 or CD8 T cells, the recipients received CD4-depleting or CD8-depleting mAb. We confirmed that survival of skin allograft was markedly prolongated in the two-signal blockade-treated group. In depletion study, anti-CD45RB, anti-CD154 and CD4-depleting mAb-treated group showed acute rejection of skin allograft in contrast to CD8-depleting group treated with the two-signal blockade. In the group treated with the two-signal blockade, the proportions of CD4+CD45RB(low)and CD8+CTLA-4 regulatory T cells were increased while effector CD8+ T cells, including IFN-gamma-secreting and CD8+CD62L(low)T cells, were decreased when compared with non-treated group. In contrast, the CD4-depleted group treated with the two-signal blockade resulted in recovery from immunoregulatory effects of two-signal blockade. In addition, results of IL-4 and IL-10 production were also showed CD4-dependence. Therefore, the two-signal blockade is accompanied by CD4-dependent mechanisms in allogeneic skin transplantation.
Transplantation, Homologous ; T-Lymphocytes, Regulatory/cytology/immunology ; Skin Transplantation/*immunology ; Signal Transduction/drug effects/immunology ; Mice, Inbred C57BL ; Mice, Inbred BALB C ; Mice ; Male ; Lymphocyte Depletion ; Lymphocyte Activation/immunology ; Interleukin-4/biosynthesis ; Interleukin-10/biosynthesis ; Graft Rejection/*immunology/prevention & control ; Flow Cytometry ; Cytotoxicity, Immunologic/immunology ; CD8-Positive T-Lymphocytes/cytology/immunology/metabolism ; CD40 Ligand/*immunology ; CD4-Positive T-Lymphocytes/cytology/immunology/metabolism ; Antigens, CD45/*immunology ; Antigens, CD4/*immunology ; Antibodies, Monoclonal/administration & dosage/*pharmacology ; Antibodies, Blocking/administration & dosage/pharmacology ; Animals

OBJECTIVETo analyze in vitro the effect of mesenchymal stem cells (MSCs) on secreting cytokines by T lymphocytes and ratio of CD4⁺CD25⁺ T cells from patients with immune thrombocytopenia (ITP).

METHODSHuman bone marrow-derived MSCs were isolated by Ficoll Hypaque and cultured for proliferating to passage cells. Allogeneic T lymphocytes of health adults and ITP patients were isolated from peripheral blood by Ficoll Hypaque and nylon cotton column, and the ratio of CD4⁺CD25⁺ T cells was detected by flow cytometry. Then the different amounts of 1 × 10⁴, 5 × 10⁴, 2 × 10⁵ MSCs per well treated with mitomycin as stromal feeder layers were co-cultured with above-mentioned T lymphocytes, 5 days after cocultivation, the ratio of CD4⁺CD25⁺ T cells was detected by flow cytometry and the levels of IL-2, IFN-γ, IL-4, IL-10 were measured by enzyme- linked immune sorbent assay (ELISA).

RESULTSAfter co-cultured with 2 × 10⁵ MSCs for 5 days, the ratio of CD4⁺CD25⁺ T cells and CD4⁺CD25⁺/CD4⁺ were significantly higher than of separate T lymphocytes in ITP patients [(4.56 ± 0.70)% vs (2.24 ± 0.81)%, (9.91 ± 1.18)% vs (4.08 ± 1.17)%, respectively] (P<0.05). To compare with separate T lymphocytes in ITP patients, the cytokine concentrations of IL-2 and IFN-γ from the culture supernatants significantly reduced from (280.47 ± 17.33) pg/ml to (97.21 ± 12.07) pg/ml and from (129.33 ± 16.34) pg/ml to (72.75 ± 7.81) pg/ml, respectively. In contrast, the cytokine concentrations of IL-4 and IL-10 increased from (16.34 ± 2.60) pg/ml to (37.98 ± 4.05) pg/ml and from (54.78 ± 5.62) pg/ml to (113.77 ± 5.68) pg/ml, respectively.

CONCLUSIONMSCs significantly inhibited the cytokine levels of IL-2 and IFN-γ secreted by Th1 cells and promoted the releases of IL-4 and IL-10 by Th2 cells in ITP , thereby regulating the balance between Th1 and Th2 reaction, as well as up-regulating the expression of CD4⁺CD25⁺ T cells in vitro,then induced the immunologic tolerance of ITP.

Adolescent ; Adult ; CD4-Positive T-Lymphocytes ; secretion ; Cells, Cultured ; Female ; Flow Cytometry ; Humans ; Interferon-gamma ; metabolism ; Interleukin-10 ; metabolism ; Interleukin-2 ; metabolism ; Interleukin-4 ; metabolism ; Male ; Mesenchymal Stromal Cells ; cytology ; Middle Aged ; Thrombocytopenia ; metabolism ; Young Adult

OBJECTIVETo explore the biological characteristic of third-party-derived tolerogenic DC(tDC) and the influence of third-party-derived tDC on acute graft-versus-host-disease (aGVHD) following allogeneic bone marrow transplantation (allo-BMT) in mice.

METHODStDC from bone marrow cells of D1 mice was cultured with low doses of GM-CSF, IL-10 and TGF-β1D1. The phenotype, expression of cytokines and function associated molecules were identified with FACS and RT-PCR. Mixed lymphocyte reaction was applied to analyze the influence of third-party-derived tDC on allo-CD4(+)T cells proliferation in vitro. Different doses of D1-tDC were adoptive transferred in the aGVHD model in allogeneic BMT which B6 mice as donors and D2 mice as recipients. Survival time, clinical GVHD score and the levels of Th1/2 cytokines in serum were monitored after allo-BMT using the aGVHD model as control.

RESULTStDC expressed lower levels of MHC II and co-stimulatory molecules, such as CD80, CD86 and CD40, even when stimulated by LPS. The results by RT-PCR indicated that tDC expressed low levels of IL-12p40 and high levels of immunosuppressive molecules, such as IL-10, TGF-β, Fas Ligand, indoleamine 2, 3-dioxygenase (IDO) and arginase. In the allogeneic MLR, third-party tDC suppressed allo-CD4(+)T cells proliferation, which was relative to the dose of tDC. In the B6→D2 mouse model, all aGVHD mice died within 18 days. Remarkably, if 10(4) third-party tDC were transferred, 60% mice survived at least 60 days. When the doses of tDC were reduced to 10(3) cells, only 20% of mice survived day 60, and when increased tDC to 10(5), all of the mice died within day 37 after allo-BMT. The cytokine levels in serum indicated that 10(4) tDC-treated mice secreted in vivo high level of IL-10 21d after BMT (P < 0.05), the levels of IL-10 in 10(3), 10(4) and 10(5) tDC-treated mice were (114.23 ± 7.78), (646.18 ± 212.02), (121.97 ± 10.47) ng/L, respectively.

CONCLUSIONThird-party tDC could suppress allo-CD4(+)T cells proliferation in vitro and prevent aGVHD in allogeneic BMT mode, which may be mediated by modulating tolerogenic cytokines secretion, such as IL-10. And this effect was associated with the dose of tDC. Adoptive therapy by transfusing third-party tDC cultured with low doses of GM-CSF, IL-10 and TGF-β1 could significantly prolong the survival of recipients and prevent aGVHD in allogeneic BMT.

Animals ; Bone Marrow Transplantation ; adverse effects ; CD4-Positive T-Lymphocytes ; cytology ; Cell Proliferation ; Dendritic Cells ; cytology ; immunology ; metabolism ; Graft vs Host Disease ; prevention & control ; Interleukin-10 ; immunology ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Transforming Growth Factor beta1 ; immunology ; Transplantation, Homologous