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No vaccine is currently licensed against human visceral leishmaniasis (VL), a fatal CD4+ T cell immunosupressive disease against which chemotherapy is reduced to a few toxic drugs. The NH36 nucleoside hydrolase is a DNA metabolism vital enzyme present in all species. A vaccine based on such a conserved antigen could protect against both VL and cutaneous leishmaniasis, whose epidemics geographically overlap. Increased frequencies of NH36-specific IL-2+TNF-α+IFN-γ+-producing CD4+ T cells were associated with VL immune protection. the sequences of HLA-Class I and Class II T cell epitopes were predicted in the NH36 peptide sequence using the Tepitope, Propred, IEDB and NetMHCpan EL 4.1 immune informatic tools. The epitopes were synthetized and used to study their reactivity with sera samples, and to stimulate the response of PBMC of human patients cured from VL, asymptomatic individuals and healthy blood donors of a non-endemic area. Cytokine production was studied intracellularly by flow cytometry (ICS) and cytokine secretion was measured in PBMC supernatants. The HLA typing of DNA patients and the analysis of epitope conservancy in the genus were obtained. Two recombinant multiepitope proteins were designed, cloned in , expressed, purified and used for stimulation of PBMC of VL cured and asymptomatic patients. We identified fifteen NH36 conserved epitopes that correspond to promiscuous binders of HLA-DR, -DQ, -DP class II molecules, as well as HLA-A, B and C class I molecules. Collectively, these epitopes provide high worldwide population coverage of both class I and II alleles, and bound to alleles associated with VL susceptibility and resistance. VL asymptomatic individuals showed maximal frequencies of CD4+ and CD8+ multifunctional IL-2+TNF-α+IFN-γ+-producing T lymphocytes in response to these epitopes, with secretion of TNF-α, IL-1β and IL-6. Two recombinant multiepitope vaccines were designed using these epitopes linked by AAA or GPGPG spacers. Both proteins promoted CD4+ and CD8+ T cell responses in PBMC of VL cured and asymptomatic individuals. Both MultiAAA and MultiGPGPG proteins could be potentially used for universal human vaccination against leishmaniasis.

The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7, 2007-2013), the Research Infrastructures Action under grant FP7-228393 (a NADIR project); from the project AGL2010-22200-C02-01 from the Spanish Ministry of Science and Innovation; the UK's BBSRC grant BBS/E/I/00002014.

[This corrects the article DOI: 10.3389/fimmu.2016.00067.].

CD4+ T-cell responses play an important role in the immune control of the human immunodeficiency virus type 1 (HIV-1) infection and as such should be efficiently induced by vaccination. It follows that definition of HIV-1-derived peptides recognized by CD4+ T cells in association with HLA class II molecules will guide vaccine development. Here, we have characterized the fine specificity of CD4+ T cells elicited in human recipients of a candidate vaccine delivering conserved regions of HIV-1 proteins designated HIVconsv. The majority of these 19 most immunogenic regions contained novel epitopes, that is, epitopes not listed in the Los Alamos National Laboratory HIV Sequence Database, which were able in vitro to stimulate vaccinees’ CD4+ T cells to proliferate and produce interferon-γ and tumor necrosis factor-α. Accumulation of HLA class II epitopes will eventually accelerate development of HIV-1 prophylactic and therapeutic vaccines.

Neoantigens derived from tumor-specific genetic mutations might be suitable targets for cancer immunotherapy because of their high immunogenicity. In the current study, we evaluated the immunogenicity of 10 driver mutations that are frequently expressed in various cancers using peripheral blood mononuclear cells from healthy donors (n = 25). Of the 10 synthetic peptides (27-mer) derived from these mutations, the six peptides from KRAS-G12D, KRAS-G12R, KRAS-G13D, NRAS-Q61R, PIK3CA-H1047R, and C-Kit-D816V induced T cell responses, suggesting that frequent driver mutations are not always less immunogenic. In particular, immune responses to PIK3CA-H1047R, C-Kit-D816V, KRAS-G13D, and NRAS-Q61R were observed in more than 10% of the donors. All six peptides induced human leukocyte antigen (HLA) class II-restricted CD4+ T cell responses; notably, PIK3CA-H1047R contained at least two different CD4+ T cell epitopes restricted to different HLA class II alleles. In addition, PIK3CA-H1047R and C-Kit-D816V induced antigen-specific CD8+ T cells as well, indicating that they might contain both HLA class I- and class II-restricted epitopes. Since the identified neoantigens might be shared by patients with various types of cancers and are not easily lost due to immune escape, they have the potential to be promising off-the-shelf cancer immunotherapy targets in patients with the corresponding mutations.

Autoreactive CD4(+) T cells recognizing islet-derived antigens play a primary role in type 1 diabetes. Specific suppression of such cells therefore represents a strategic target for the cure of the disease. We have developed a methodology by which CD4(+) T cells acquire apoptosis-inducing properties on antigen-presenting cells after cognate recognition of natural sequence epitopes. We describe here that inclusion of a thiol-disulfide oxidoreductase (thioreductase) motif within the flanking residues of a single MHC class II-restricted GAD65 epitope induces GAD65-specific cytolytic CD4(+) T cells (cCD4(+) T). The latter, obtained either in vitro or by active immunization, acquire an effector memory phenotype and lyse APCs by a Fas-FasL interaction. Furthermore, cCD4(+) T cells eliminate by apoptosis activated bystander CD4(+) T cells recognizing alternative epitopes processed by the same APC. Active immunization with a GAD65 class II-restricted thioreductase-containing T cell epitope protects mice from diabetes and abrogates insulitis. Passive transfer of in vitro-elicited cCD4(+) T cells establishes that such cells are efficient in suppressing autoimmunity. These findings provide strong evidence for a new vaccination strategy to prevent type 1 diabetes.

Humans vaccinated with hepatitis B virus (HBV) surface antigen (HBsAg) sometimes develop humoral and cellular immunity to HBV proteins such as core and polymerase that are not vaccine components, providing indirect evidence that vaccine-induced immunity is not sterilizing. We previously described CD4⁺ T-cell immunity against HBsAg and polymerase in chimpanzees after vaccination and HBV challenge. Here, vaccinated chimpanzees with protective levels of anti-HBsAg antibodies were rechallenged with HBV after antibody-mediated CD4⁺ T-cell depletion. HBV DNA was detected in liver for at least 3 months after rechallenge, but virus replication was suppressed, as revealed by the absence of HBV DNA and HBsAg in serum. These observations provide direct virological evidence for nonsterilizing immunity in individuals with anti-HBsAg antibodies and are consistent with translation of HBV proteins to prime immune responses. They also indicate that CD4⁺ T cells were not required for suppression of HBV replication in previously vaccinated individuals.

Background The Phlebotomus papatasi salivary protein PpSP15 was shown to protect mice against Leishmania major , suggesting that incorporation of salivary molecules in multi-component vaccines may be a viable strategy for anti- Leishmania vaccines. Methods Here, we investigated PpSP15 predicted amino acid sequence variability and mRNA profile of P. papatasi field populations from the Middle East. In addition, predicted MHC class II T-cell epitopes were obtained and compared to areas of amino acid sequence variability within the secreted protein. Results The analysis of PpSP15 expression from field populations revealed significant intra- and interpopulation variation.. In spite of the variability detected for P. papatasi populations, common epitopes for MHC class II binding are still present and may potentially be used to boost the response against Le. major infections. Conclusions Conserved epitopes of PpSP15 could potentially be used in the development of a salivary gland antigen-based vaccine.

Abrogating an unwanted immune response toward a specific antigen without compromising the entire immune system is a hoped-for goal in immunotherapy. Instead of manipulating dendritic cells and suppressive regulatory T cells, depleting effector T cells or blocking their co-stimulatory pathways, we describe a method to specifically inhibit the presentation of an antigen eliciting an unwanted immune reaction. Inclusion of an oxidoreductase motif within the flanking residues of MHC class II epitopes polarizes CD4(+) T cells to cytolytic cells capable of inducing apoptosis in antigen presenting cells (APCs) displaying cognate peptides through MHC class II molecules. This novel function results from an increased synapse formation between both cells. Moreover, these cells eliminate by apoptosis bystander CD4(+) T cells activated at the surface of the APC. We hypothesize that they would thereby block the recruitment of cells of alternative specificity for the same autoantigen or cells specific for another antigen associated with the pathology, providing a system by which response against multiple antigens linked with the same disease can be suppressed. These findings open the way toward a novel form of antigen-specific immunosuppression.

Abrogating an unwanted immune response towards a specific antigen without compromising the entire immune system is a hoped-for goal in immunotherapy. Instead of manipulating dendritic cells and suppressive regulatory T cells, depleting effector T cells or blocking their co-stimulatory pathways, we describe a method to specifically inhibit the presentation of an antigen eliciting an unwanted immune reaction. Inclusion of an oxido-reductase motif within the flanking residues of MHC-class II epitopes polarizes CD4+ T cells to cytolytic cells capable of inducing apoptosis in antigen presenting cells (APC) displaying cognate peptides through MHC class II molecules. This novel function results from an increased synapse formation between both cells. Moreover, these cells eliminate by apoptosis bystander CD4+ T cells activated at the surface of the APC. We hypothesize that they would thereby block the recruitment of cells of alternative specificity for the same autoantigen or cells specific for another antigen associated with the pathology, providing a system by which response against multiple antigens linked with the same disease can be suppressed. These findings open the way towards a novel form of antigen-specific immunosuppression.