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CD4+ T Cell Responses (cd4+ t + cell_response)
Selected AbstractsRecognition of coagulation factor VIII by CD4+ T cells of healthy humansJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2003G-L. Hu Summary., Hemophilia A patients treated with coagulation factor (F)VIII may develop an anti-FVIII immune response. Anti-FVIII antibodies may occur also in healthy subjects. To understand the extent to which an immune response to FVIII occurs in healthy subjects, we investigated the proliferative response of blood CD4+ T cells from 90 blood donors to FVIII and to pools of overlapping synthetic peptides spanning the sequences of individual FVIII domains (A1,A3, C1,C2). Most subjects responded to FVIII and several FVIII domains. Men had stronger responses to FVIII than women, and older subjects than younger subjects. The domain-induced responses were weaker than the FVIII-induced responses, yet their intensity in individual subjects correlated with that of the response to FVIII. We examined whether Th1 and/or Th2 cells responded to FVIII in 68 subjects, by determining the CD4+ T cells that secreted interferon-, (IFN-,) or interleukin (IL)-5 after stimulation with FVIII: 25 subjects had FVIII-specific IFN-,-secreting cells, and seven of them had also FVIII-specific IL-5-secreting cells. None had only IL-5-secreting cells. Thus, a CD4+ T cell response to FVIII, which first involves Th1 cells, is common among subjects with a normal procoagulant function. [source] Genetic approaches for the induction of a CD4+ T cell response in cancer immunotherapyTHE JOURNAL OF GENE MEDICINE, Issue 6 2005Aude Bonehill Abstract Recently, it has become more and more obvious that not only CD8+ cytotoxic T lymphocytes, but also CD4+ T helper cells are required for the induction of an optimal, long-lasting anti-tumor immune response. CD4+ T helper cells, and in particular IFN-,-secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer-specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti-cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide-binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development. Copyright © 2005 John Wiley & Sons, Ltd. [source] Enhanced Th1 and Th17 responses and arthritis severity in mice with a deficiency of myeloid cell,specific interleukin-1 receptor antagonistARTHRITIS & RHEUMATISM, Issue 2 2010Céline Lamacchia Objective The balance between interleukin-1 (IL-1) and its specific inhibitor, the IL-1 receptor antagonist (IL-1Ra), plays a major role in the development of arthritis. The purpose of this study was to investigate the role of IL-1Ra produced specifically by myeloid cells in the control of collagen-induced arthritis (CIA) by using myeloid cell,specific IL-1Ra,deficient mice (IL-1Ra,M). Methods IL-1Ra,M mice were generated by using the loxP/Cre recombinase system. CIA was induced in IL-1Ra,M mice and littermate control mice by a single immunization with bovine type II collagen (CII) in Freund's complete adjuvant. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (DLN) cell responses were examined ex vivo, and ankle extracts were used in the quantification of cytokines and chemokines. Results Clinical and histopathologic evaluations revealed an early disease onset and a severe form of CIA in IL-1Ra,M mice. This was characterized by increased production of interferon-, (IFN,) and IL-17 by CII-stimulated DLN cells. We also observed that the CII-specific CD4+ T cell response shifted in vivo, from a dominant Th1 response early in the course of the arthritis to the presence of both Th1 and Th17 cytokines later in the disease course. Interestingly, IL-1Ra levels were higher in the arthritic joints of IL-1Ra,M mice as compared with the controls, indicating that nonmyeloid cells strongly contribute to the local production of IL-1Ra. However, this enhanced IL-1Ra production was not sufficient to limit joint inflammation and tissue damage. Conclusion Our results suggest that myeloid cell,derived IL-1Ra plays a critical role in the control of the development and the severity of CIA by modulating Th1 and Th17 responses in lymphoid organs. [source] Differential capacity of T cell priming in naive donors of promiscuous CD4+ T cell epitopes of HCV NS3 and Core proteinsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2007Florence Abstract To understand the inter-individual and virus-independent variability of CD4+ T cell responses to HCV components, we evaluated the effect on these responses of HLA II molecules in uninfected healthy donors. Using HLA II-specific binding assays, we identified, in the Core and NS3 proteins, 21 long fragments and 24 15-mer peptides that bound to four to eight of the most preponderant HLA II molecules. We then evaluated the priming capacity of eight long promiscuous peptides in 12 HLA-unrelated healthy donors. The NS3 1250,1264 peptide primed T cells in all the naive donors, while five others were stimulating in at least half of the individuals. We also report sequences that bind to multiple HLA II molecules but are weakly immunogenic. We therefore conclude that (i) broad HLA II specificity is only a prerequisite for a peptide to be stimulating in multiple individuals, and (ii) promiscuous peptides widely differ in their capacity to prime CD4+ T cells from uninfected healthy donors. We suggest that these priming differences result from inter-individual variations in the peptide-specific T cell repertoire. Interestingly, five of the most immunogenic peptides we identified correspond to frequently targeted T cell epitopes in infected patients. [source] RNA-containing adenovirus/polyethylenimine transfer complexes effectively transduce dendritic cells and induce antigen-specific T cell responsesTHE JOURNAL OF GENE MEDICINE, Issue 4 2004Tatjana C. Gust Abstract Background Dendritic cells (DCs) are the most potent antigen-presenting cells in initiating primary immune responses. Given the unique properties of DCs, gene-modified DCs represent a particularly attractive approach for immunotherapy of diseases such as cancer. Methods Gene-modified DCs were obtained by a receptor-mediated gene delivery system using adenovirus (Ad) particles as ligand and RNA or DNA condensed by polyethylenimine (PEI). In vitro transcribed polyadenylated or non-polyadenylated RNA was used. RNA-transduced DCs were generated expressing chicken ovalbumin (OVA) or chimeric constructs thereof, and compared with DNA-transduced DCs. Results Ad/PEI transfection complexes efficiently delivered RNA into DCs. Such RNA-transduced DCs induced OVA-specific T cell responses more effectively than DNA-transduced DCs. Furthermore, DCs transduced with polyadenylated RNA were more potent in stimulating CD4+ and CD8+ T cell responses than DCs transduced with non-polyadenylated RNA and this was particularly important for CD4+ T cell responses. Conclusions Ad/PEI/RNA transfection is an efficient means for generating RNA-transduced DCs and for stimulating antigen-specific T cell responses. Polyadenylation of RNA enhances CD8+ T cell responses and is essential for CD4+ T cell responses. Copyright © 2004 John Wiley & Sons, Ltd. [source] HLA,DR1001 presents "altered-self" peptides derived from joint-associated proteins by accepting citrulline in three of its binding pocketsARTHRITIS & RHEUMATISM, Issue 10 2010Eddie A. James Objective HLA,DRB1*1001 (DR1001) is a shared epitope allele associated with rheumatoid arthritis (RA). The present study was undertaken to assess the capacity of DR1001 to accommodate citrulline in its binding pockets and to identify citrullinated T cell epitopes derived from joint-associated proteins. Methods The binding of peptide derivatives containing citrulline, arginine, and other amino acid substitutions was measured. A prediction algorithm was developed to identify arginine-containing sequences from joint-associated proteins that preferentially bind to DR1001 upon citrullination. Unmodified and citrullinated versions of these sequences were synthesized and were utilized to stimulate CD4+ T cells from healthy subjects and RA patients. Responses were measured by class II major histocompatibility complex tetramer staining and confirmed by isolating CD4+ T cell clones. Results DR1001 accepted citrulline, but not arginine, in 3 of its anchoring pockets. The prediction algorithm identified sequences that preferentially bound to DR1001 with arginine replaced by citrulline. Three of these sequences elicited CD4+ T cell responses. T cell clones specific for these sequences proliferated only in response to citrullinated peptides. Conclusion Conversion of arginine to citrulline generates "altered-self" peptides that can be bound and presented by DR1001. Responses to these peptides implicate the corresponding proteins (fibrinogen ,, fibrinogen ,, and cartilage intermediate-layer protein) as relevant antigens. The finding of preferential responses to citrullinated sequences suggests that altered peptide binding affinity due to this posttranslational modification may be an important factor in the initiation or progression of RA. As such, measuring responsiveness to these peptides may be useful for immunologic monitoring. [source] High-affinity human leucocyte antigen class I binding variola-derived peptides induce CD4+ T cell responses more than 30 years post-vaccinia virus vaccinationCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009M. Wang Summary Interferon-, secreting T lymphocytes against pox virus-derived synthetic 9-mer peptides were tested by enzyme-linked immunospot in peripheral blood of individuals vaccinated with vaccinia virus more than 30 years ago. The peptides were characterized biochemically as high-affinity human leucocyte antigen (HLA) class I binders (KD , 5 nM). However, five of the individuals tested did not show typical CD8+ T cell-mediated HLA class I-restricted responses. Instead, these donors showed CD4+ T cell-dependent responses against four of a total of eight antigenic 9-mer peptides discovered recently by our group. These latter responses were blocked specifically in the presence of anti-HLA class II antibody. We conclude that long-lived memory responses against pox virus-derived 9-mer peptides, with high binding affinity for HLA class I molecules, are mediated in some cases by CD4+ T cells and apparently restricted by HLA class II molecules. [source] Human immunodeficiency virus (HIV)-specific T helper responses fail to predict CD4+ T cell decline following short-course treatment at primary HIV-1 infectionCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2008J. Fox Summary Early anti-retroviral treatment (ART) in primary human immunodeficiency virus (HIV) infection (PHI) may have unique, restorative immunological and virological benefits which could enhance clinical outcomes. However, the sustainability of these HIV-specific immune responses and their impact on clinical outcome remains unclear. We present a 3-year longitudinal clinical and immunological follow-up of a single-arm, prospective study assessing the long-term impact of a short-course of ART (SCART) during PHI. Twenty-eight subjects with defined PHI received 3 months of SCART at HIV-1 seroconversion. HIV-specific interferon-,+ CD4+ T cell responses, CD4 cell counts and plasma viral loads were assessed prospectively. Clinical outcome was defined as the time taken from PHI to a fall in CD4 cell counts <350 cells/,l on two or more occasions. Of 28 patients, 25 (89%) had detectable HIV-specific CD4+ helper responses at baseline. Five of 11 (45%) patients had preserved HIV-specific CD4+ responses 3 years after stopping SCART. Neither the presence nor magnitude of HIV-1-specific T helper responses either at baseline or 3 years following SCART cessation predicted clinical outcome. Rebound viraemia associated with stopping SCART did not diminish HIV-1-specific CD4+ responses. Long-term (>3 years) preservation of virus-specific CD4+ cells occurred in 45% of patients receiving SCART in PHI. There was no correlation between either the presence or magnitude of these responses and clinical outcome. [source] Generation of cytotoxic T cell responses directed to human leucocyte antigen Class I restricted epitopes from the Aspergillus f16 allergenCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2005G. Ramadan Summary Invasive aspergillosis (IA) is a major cause of infection-related mortality in patients with haematological malignancies, especially in recipients of haematopoietic stem cell transplants. We have prepared overlapping pentadecapeptides (11-aa overlap with previous peptide) spanning the entire 427-aa coding region of the Aspergillus allergen, Asp f16 shown previously in mice to induce Th1-type cell responses in vivo and in humans to induce proliferative and cytotoxic CD4+ T cell responses. Mature dendritic cells (DC) pulsed with a complete pool of peptides were used to generate T cell lines. Two lines from HLA-B*3501+ donors were found to be strongly cytotoxic to autologous Asp f16-peptide pool- and Aspergillus culture extract-pulsed targets after 4,5 weekly primings. Cytotoxic T lymphocyte (CTL) culture supernatant killed Aspergillus conidia, and cells directly killed Aspergillus hyphae. Cytotoxic activity and interferon (IFN)-, production were mediated exclusively by CD8+ T cells in response to pool-pulsed targets. Interleukin (IL)-4 production was not detected. CTL activity was restricted by HLA-B*3501 and based on peptide prediction programmes was most probably directed to YFKYTAAAL (YFK), LPLCSAQTW (LPL) and GTRFPQTPM (GTR) in one donor, while only LPL was recognized by CTL from the second donor. Pool-pulsed B*3503+ BLCL but not B*3502+ or B*3508+ BLCL presented peptide to donor no. 1. B*3503+ BLCL presented YFK and to a lesser extent GTR, but not peptide LPL. Our data show that in addition to our previously identified Class II restricted peptide response, DC pulsed with a pentadecapeptide pool from Asp f16 are capable of inducing polyclonal, HLA-Class I-restricted, Aspergillus -specific T cells that may be capable of conferring immunity to IA. [source] | ||||||||||