scholarly journals B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction

2018 ◽  
Vol 115 (12) ◽  
pp. 3126-3131 ◽  
Author(s):  
Ling Chen ◽  
Takeshi Azuma ◽  
Weiwei Yu ◽  
Xu Zheng ◽  
Liqun Luo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Response ◽  
Tumor Escape ◽  
Immune Functions ◽  
Adaptive Resistance ◽  
Multiple Tumor ◽  
Ctl Responses

Induced B7-H1 expression in the tumor microenvironment initiates adaptive resistance, which impairs immune functions and leads to tumor escape from immune destruction. Antibody blockade of the B7-H1/PD-1 interaction overcomes adaptive resistance, leading to regression of advanced human cancers and survival benefits in a significant fraction of patients. In addition to cancer cells, B7-H1 is expressed on dendritic cells (DCs), but its role in DC functions is less understood. DCs can present multiple antigens (Ags) to stimulate dominant or subdominant T cell responses. Here, we show that immunization with multiple tumor Ag-loaded DCs, in the absence of B7-H1, vastly enhances cytotoxic T lymphocyte (CTL) responses to dominant Ag. In sharp contrast, CTL responses to subdominant Ag were paradoxically suppressed, facilitating outgrowth of tumor variants carrying only subdominant Ag. Suppressed CTL responses to subdominant Ag are largely due to the loss of B7-H1–mediated protection of DCs from the lysis of CTL against dominant Ag. Therefore, B7-H1 expression on DCs may help maintain the diversity of CTL responses to multiple tumor Ags. Interestingly, a split immunization approach, which presents dominant and subdominant Ags with different DCs, promoted CTL responses to all Ags and prevented tumor escape in murine tumor models. These findings have implications for the design of future combination cancer immunotherapies.

scholarly journals Acute Resolving Woodchuck Hepatitis Virus (WHV) Infection Is Associated with a Strong Cytotoxic T-Lymphocyte Response to a Single WHV Core Peptide

2007 ◽  
Vol 81 (13) ◽  
pp. 7156-7163 ◽  
Author(s):  
Ina Frank ◽  
Claudia Budde ◽  
Melanie Fiedler ◽  
Uta Dahmen ◽  
Sergei Viazov ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Cell Response ◽  
Cytotoxic T Lymphocyte ◽  
Hepatitis Virus ◽  
Immunological Response ◽  
T Cell Response ◽  
Woodchuck Hepatitis Virus ◽  
Core Peptide ◽  
Ctl Responses

ABSTRACT Woodchucks infected with woodchuck hepatitis virus (WHV) are an excellent model for studying acute, self-limited and chronic hepadnaviral infections. Defects in the immunological response leading to chronicity are still unknown. Specific T-helper cell responses to WHV core and surface antigens (WHcAg and WHsAg, respectively) are associated with acute resolving infection; however, they are undetectable in chronic infection. Up to now, cytotoxic T-lymphocyte (CTL) responses could not be determined in the woodchuck. In the present study, we detected virus-specific CTL responses by a CD107a degranulation assay. The splenocytes of woodchucks in the postacute phase of WHV infection (18 months postinfection) were isolated and stimulated with overlapping peptides covering the whole WHcAg. After 6 days, the cells were restimulated and stained for CD3 and CD107a. One peptide (c96-110) turned out to be accountable for T-cell expansion and CD107a staining. Later, we applied the optimized degranulation assay to study the kinetics of the T-cell response in acute WHV infection. We found a vigorous T-cell response against peptide c96-110 with peripheral blood cells beginning at the peak of viral load (week 5) and lasting up to 15 weeks postinfection. In contrast, there was no T-cell response against peptide c96-110 detectable in chronically WHV-infected animals. Thus, with this newly established flow cytometric degranulation assay, we detected for the first time virus-specific CTLs and determined one immunodominant epitope of WHcAg in the woodchuck.

scholarly journals Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7

2016 ◽  
Vol 25 (10) ◽  
pp. 774-787 ◽  
Author(s):  
Matthew M. Halpert ◽  
Vanaja Konduri ◽  
Dan Liang ◽  
Yunyu Chen ◽  
James B. Wing ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
T Lymphocyte ◽  
Cell Response ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Response

scholarly journals Cytotoxic T-Lymphocyte Antigen 4 Gene and Recovery from Hepatitis B Virus Infection

2004 ◽  
Vol 78 (20) ◽  
pp. 11258-11262 ◽  
Author(s):  
Chloe L. Thio ◽  
Timothy L. Mosbruger ◽  
Richard A. Kaslow ◽  
Christopher L. Karp ◽  
Steffanie A. Strathdee ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
T Lymphocyte ◽  
Cell Response ◽  
Cytotoxic T Lymphocyte ◽  
Viral Persistence ◽  
T Cell Response ◽  
Hbv Infection ◽  
B Virus

ABSTRACT Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an inhibitory T-cell receptor expressed by activated and regulatory T cells. We hypothesized that single-nucleotide polymorphisms (SNPs) in the gene encoding CTLA-4 may affect the vigor of the T-cell response to hepatitis B virus (HBV) infection, thus influencing viral persistence. To test this hypothesis, we genotyped six CTLA4 SNPs, from which all frequent haplotypes can be determined, using a large, matched panel of subjects with known HBV outcomes. Haplotypes with these SNPs were constructed for each subject using PHASE software. The haplotype distribution differed between those with viral persistence and those with clearance. Two haplotypes were associated with clearance of HBV infection, which was most likely due to associations with the SNPs −1722C (odds ratio [OR] = 0.60, P = 0.06) and +49G (OR = 0.73, P = 0.02). The wild-type haplotype, which contains an SNP leading to a decreased T-cell response (+6230A), was associated with viral persistence (OR = 1.32, P = 0.04). These data suggest that CTLA4 influences recovery from HBV infection, which is consistent with the emerging role of T regulatory cells in the pathogenesis of disease.

scholarly journals Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by the Salmonella Type III Secretion Antigen Delivery System

2003 ◽  
Vol 77 (4) ◽  
pp. 2400-2409 ◽  
Author(s):  
David T. Evans ◽  
Li-Mei Chen ◽  
Jacqueline Gillis ◽  
Kuei-Chin Lin ◽  
Brian Harty ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Replication ◽  
T Lymphocyte ◽  
Type Iii Secretion ◽  
Cytotoxic T Lymphocyte ◽  
Rhesus Macaques ◽  
Secretion System ◽  
Type Iii ◽  
Immunodeficiency Virus ◽  
Ctl Responses

ABSTRACT Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested ΔphoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01 + macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag181-189 epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag181-189-specific CD8+ T-cell responses in peripheral blood. A significant percentage of the Gag181-189-specific T-cell population in each animal also expressed the intestinal homing receptor α4β7. Additionally, Gag181-189-specific CD8+ T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model.

Residual Lymphocytes in GM-CSF and IL-15 Differentiated Monocyte-Derived Dendritic Cells Enables Cytotoxic T Lymphocyte Responses.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4907-4907
Author(s):  
Melinda Y. Hardy ◽  
Andrew J. Kassianos ◽  
Ray Wilkinson ◽  
Annelie Vulink ◽  
Derek N.J. Hart ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Small Population ◽  
Lymphoid Cells ◽  
Gm Csf ◽  
Hla Dr ◽  
Ifn Γ ◽  
Human Dendritic Cells ◽  
Ctl Responses

Abstract We investigated the capacity of IL-15 to differentiate human dendritic cells (DC) from monocytes in the presence of GM-CSF (IL-15 MoDC) and compared them with MoDC differentiated in IL-4 and GM-CSF (IL-4 MoDC) as used in many immunotherapy protocols. IL-15 MoDC expressed higher levels of CD40 and HLA-DR and importantly, induced MART-1 specific cytotoxic T lymphocyte (CTL) responses with superior lytic capacity, when compared to IL-4 MoDC. In response to activation, IL-15 MoDC secreted high levels of IFN-γbut low or no IL-12, whereas IL-4 MoDC secreted high IL-12 but low or no IFN-γ. Using an IFN-γ blocking antibody, we demonstrated that IFN-γ production by the IL-15 MoDC did not account for the superior CTL responses induced. Despite immunoselecting monocytes to greater than 97% purity prior to DC differentiation, we noticed a small population (1–2%) of CD56+ and CD3+ lymphocytes in the IL-15 MoDC preparations that were less prominent in IL-4 MoDC differentiated from the same monocytes. Removal of the residual lymphocytes from monocytes prior to differentiation into IL-15 MoDC diminished their capacity to induce CTL but did not affect the expression of HLA-DR or CD40. These data suggest that IL-15-dependent cross-talk between the small lymphoid populations present and DC, during DC differentiation from monocytes results in superior CTL priming that is independent of IL-12 and IFN-γ. Based on these results, appropriately manufactured IL-15 MoDC preparations containing defined numbers of lymphoid cells should be considered for immunotherapy.

scholarly journals Oral Vaccination with Attenuated Salmonella enterica Strains Encoding T-Cell Epitopes from Tumor Antigen NY-ESO-1 Induces Specific Cytotoxic T-Lymphocyte Responses

2010 ◽  
Vol 17 (6) ◽  
pp. 889-894 ◽  
Author(s):  
Jia-Zi Meng ◽  
Yu-Jun Dong ◽  
He Huang ◽  
Shuang Li ◽  
Yi Zhong ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Salmonella Enterica ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Response ◽  
Target Antigen ◽  
Immune Recognition ◽  
T Cell Epitopes ◽  
Replacement Method

ABSTRACT Bacterial fimbriae can accept foreign peptides and display them on the cell surface. A highly efficient gene replacement method was used to generate peptide vaccines based on Salmonella enterica serovar Typhimurium SL3261. The T-cell epitopes (NY-ESO-1 p157-165 and p157-167) from NY-ESO-1, which is a promising target antigen in patients for the specific immune recognition of cancer, were incorporated into the gene encoding AgfA (the major subunit protein of thin aggregative fimbriae of Salmonella) by replacing an equal length of the DNA segment. To improve cytotoxic T-lymphocyte recognition, both termini of the peptide were flanked by double alanine (AA) residues. Immunofluorescence microscopy with AgfA-specific antiserum verified the expression of chimeric AgfA, which was also proved by a Congo red binding assay. Oral immunizations of HLA-A*0201 transgenic mice with recombinant SL3261 strains encoding NY-ESO-1 p157-165 or p157-167 induced NY-ESO-1 p157-165-specific CD8+ T cells, detected by an HLA-A*0201 pentamer, and induced a T-cell response detected by an enzyme-linked immunospot assay. The Salmonella fimbrial display system was efficient at the induction of an antitumor cellular immune response in vivo, providing a new strategy for the development of efficient cancer vaccinations.

Sign in / Sign up

Export Citation Format

Share Document