TY  - JOUR
AB  - T-cell development in the thymus is dependent on the continual colonization by bone-marrow derived progenitor cells. Once inside the thymus, progenitors undergo a series of well-defined differentiation events, including lineage commitment, somatic recombination of T-cell receptor (TCR) gene loci, and selection of clones with productively recombined yet non-autoreactive TCRs. Cell-cell interactions, cytokine signals, transcriptional as well as epigenetic programs controlling T-cell development are comparatively well-characterized. In contrast, the contribution of post-transcriptional control and its underlying mechanisms remain largely elusive. Here, we summarize recent advances in our understanding of post-transcriptional regulation of T-cell development, focussing on microRNAs (miRNAs) and RNA-binding proteins (RBPs). We highlight the current challenges, and how they can potentially be overcome with evolving sophisticated methodology to enable a thorough mechanistic understanding and decipher the regulatory networks operating in the gene expression programs of T-cell development.
AU  - Krueger, A.*
AU  - Łyszkiewicz, M.*
AU  - Heissmeyer, V.
C1  - 65065
C2  - 52655
SP  - 1-12
TI  - Post-transcriptional control of T-cell development in the thymus.
JO  - Immunol. Lett.
VL  - 247
PY  - 2022
SN  - 0165-2478
ER  - 

TY  - JOUR
AB  - Somatic hypermutation (SHM) diversifies the rearranged immunoglobulin variable (V) region gene in B cells, contributing to affinity maturation of antibodies. It is believed that SHM is generated either by direct replication or by error-prone repair systems resolving V region DNA lesions caused directly or indirectly by cytidine deaminase AID. In accord with a part of these mechanisms, it was reported that SHM is associated with staggered double-strand DNA breaks (DSBs) occurring in the rearranged V regions. However, endonucleases responsible for the DSBs remain elusive. Here we show that DNase gamma, a member of DNase I family endonucleases, contributes to the generation of SHM including point mutation, and nucleotide insertion and deletion in chicken DT40 B cell line. DNase gamma also contributes to the generation of staggered DSBs in the rearranged V region. These results raise a possibility that DNase gamma is involved in the V gene mutation machinery.
AU  - Okamoto, N.*
AU  - Okamoto, M.*
AU  - Araki, S.*
AU  - Arakawa, H.
AU  - Mizuta, R.*
AU  - Kitamura, D.*
C1  - 726
C2  - 26974
SP  - 22-30
TI  - Possible contribution of DNase γ to immunoglobulin V gene diversification.
JO  - Immunol. Lett.
VL  - 125
IS  - 1
PB  - Elsevier Science
PY  - 2009
SN  - 0165-2478
ER  - 

TY  - JOUR
AB  - Tumors often induce tolerance in the immune system, which may contribute to the limited success of clinical vaccination against tumors. In order to develop strategies for overcoming tumor tolerance we have developed an inducible mouse model of autochthonus hepatocellular carcinoma growth, which relates more closely to the clinical situation than transplantation tumors. These so-called AST mice harbour a construct consisting of the hepatocyte-specific albumin promoter, a loxP flanked stop-cassette, and the oncogene SV40 large T antigen (Tag). By intravenous application of an adenovirus encoding Cre recombinase the stop cassette was excised, thereby inducing Tag expression and formation of hepatoma nodules in a dose-dependent fashion in about 3 months. Non-induced AST mice showed tumor tolerance, as demonstrated by the failure to reject Tag-positive transplantation tumors and the inability to mount CTL following Tag immunization. Dendritic cell-based immunization with an agonist Tag peptide was able to overcome tolerance and resulted in marked CTL activity against naturally occurring Tag epitopes. importantly, vaccination with the agonist peptide prevented growth of the autochthonous liver tumors and significantly prolonged survival of the animals. Our findings demonstrate that agonist peptides can be used in immunization protocols for breaking of tolerance and induction of CTL that mediate effective anti-tumor responses. In addition, the inducible hepatoma model described here can be used for the design of therapeutic strategies against hepatocellular carcinoma.
AU  - Stahl, S.*
AU  - Sacher, T.*
AU  - Bechtold, A.*
AU  - Protzer, U.
AU  - Ganss, R.*
AU  - Hämmerling, G.J.*
AU  - Arnold, B.*
AU  - Garbi, N.*
C1  - 1073
C2  - 26935
SP  - 31-37
TI  - Tumor agonist peptides break tolerance and elicit effective CTL responses in an inducible mouse model of hepatocellular carcinoma.
JO  - Immunol. Lett.
VL  - 123
IS  - 1
PB  - Elsevier Science Bv
PY  - 2009
SN  - 0165-2478
ER  - 

TY  - JOUR
AB  - Monocyte heterogeneity has been studied extensively in man but only recently tools have been developed to study blood monocyte populations in the mouse. We have used the MacGreen mouse model, which expresses the green fluorescent protein under the control of the promoter of the murine M-CSF receptor (CSF1 receptor, c-fms). Since both monocytes and granulocytes show GFP expression in this model the latter cells were excluded by staining with the Ly6G granulocyte marker. GFP(+) Ly6G(-) blood monocytes were found to account for an average of 246+/-121cells/mul in these mice. These monocytes can be subdivided into CD43(+) GR-1(+) cells and CD43(++) GR-1(-) cells, with the latter cells accounting for 140+/-77cells/mul, i.e. about 60% of all blood monocytes. After intraperitoneal injection of lipopolysaccharide (LPS) both blood monocyte subpopulations were depleted. The same was true after intranasal infection with Streptococcus pneumoniae but here the CD43(++) subpopulation was preferentially reduced to 4cells/mul. For the study of TNF expression cells were stimulated in vitro with LPS from Salmonella abortus equi in the presence of Brefeldin A followed by intracellular staining and multicolor flow cytometry. Over a dose range of 10-100ng LPS/ml, TNF protein production was significantly higher in the CD43(++) monocyte subset. At 1000ng LPS/ml 90% of all CD43(++) monocytes stained positive for TNF and in terms of fluorescence intensity TNF was 5-fold higher compared to the CD43(+) monocytes. These data indicate that the murine CD43(++) monocyte subset exhibits features of pro-inflammatory monocytes and is functionally homologeous to the human CD14(+)CD16(+) monocytes.
AU  - Burke, B.*
AU  - Ahmad, R.*
AU  - Staples, K.J.*
AU  - Snowden, R.*
AU  - Kadioglu, A.*
AU  - Frankenberger, M.
AU  - Hume, D.A.*
AU  - Ziegler-Heitbrock, L.
C1  - 1455
C2  - 25297
SP  - 142-147
TI  - Increased TNF expression in CD43(++) murine blood monocyes.
JO  - Immunol. Lett.
VL  - 118
IS  - 2
PB  - Elsevier
PY  - 2008
SN  - 0165-2478
ER  - 

TY  - JOUR
AB  - NK cells recognize target cells with reduced expression of MHC class I molecules. Human immunodeficiency virus (HIV) infection decreases MHC class I on the cell membrane. The aim of this study was to directly evaluate the role and conditions of NK cell effects in HIV seropositive patients ex vivo. Autologous HIV-infected CD4+ T cells were exposed to NK cells recognition. We discovered an increased lysis of the target cells after infection with human immunodeficiency virus-1 (HIV-1). The expression of the HIV-1 nef gene or the combined expression of nef and tat confers NK susceptibility to autologous CD4+ targets. Downregulation of MHC class I but not HLA-C or CD4 correlated with increased recognition by NK cells. The specific recognition is correlated with downregulation of MHC class I molecules on the infected target cells.
AU  - Hultström, A.L.*
AU  - Bratt, G.*
AU  - Cosma, A.
AU  - Erfle, V.
AU  - Wahren, B.*
AU  - Carbone, E.*
C1  - 23858
C2  - 31372
SP  - 155-158
TI  - Autologous cytotoxicity of natural killer cells derived from HIV-infected patients.
JO  - Immunol. Lett.
VL  - 91
IS  - 2-3
PB  - Elsevier Science
PY  - 2004
SN  - 0165-2478
ER  - 

TY  - JOUR
AB  - Since its initial clinical use in 1980, anti-TCR/CD3 monoclonal antibody (mAb) has been shown to be a potent immunosuppressive agent in the prevention of renal allograft rejections. However, toxic side effects caused by release of cytokines, predominantly from activated CD4+ T-cells, remain a major problem with the use of these reagents. Previous work has shown that this activation is mediated via antibody binding to Fcgamma receptors (FcgammaR) on host effector cells. In the present study, we have demonstrated in an in vivo mouse model that the anti-TCR/CD3 mouse mAb 7D6, as well as that from rat (17A2) and hamster (H57-597), induce a gradual depletion of host CD4+ T-cells without any apparent proliferative effects on the cells. In contrast, when treatment with these mAbs was combined with a mAb (2.4G2) that blocks the low-affinity Fcgamma receptors (FcgammaRII/III), we found that the in vivo actions of the anti-TCR/CD3 mAbs resulted in a significant expansion, rather than depletion, of CD4+ cells. The ability of 2.4G2 to reduce mAb 7D6-FcgammaR interaction was directly demonstrated in an in vitro assay system in which 2.4G2 partially suppressed 7D6-mediated T-cell responses. Taken together, our results have shown that some so-called "nonmitogenic" anti-TCR/CD3 mAbs in fact possess potent activating properties and that their mitogenic potential can be exposed by reducing their interaction with FcgammaR on host effector cells.
AU  - Kummer, U.
AU  - Zengerle, U.
AU  - Pischel, J.
AU  - Trautmann, B.
AU  - Mailhammer, R.
AU  - Sidell, N.*
C1  - 23896
C2  - 31394
SP  - 153-158
TI  - Increased in vivo mitogenicity of anti-TCR/CD3 monoclonal antibody through reduced interaction with Fcγ receptors.
JO  - Immunol. Lett.
VL  - 75
IS  - 2
PB  - Elsevier
PY  - 2001
SN  - 0165-2478
ER  -