scholarly journals Tuning antiviral CD8 T-cell response via proline-altered peptide ligand vaccination

2019 ◽  
Author(s):  
Adil Doganay Duru ◽  
Renhua Sun ◽  
Eva B. Allerbring ◽  
Jesseka Chadderton ◽  
Nadir Kadri ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
Immune Escape ◽  
Viral Escape ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Cell Recognition ◽  
Escape Variant ◽  
T Cell Recognition ◽  
Naturally Occurring

AbstractViral escape from CD8+ cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+ T cell recognition of the naturally occurring MHC-I-restricted LCMV-associated immune escape variant Y4F is restored following vaccination with a proline-altered peptide ligand (APL). The APL increases MHC/peptide (pMHC) complex stability, rigidifies the peptide and facilitates T cell receptor (TCR) recognition through reduced entropy costs. Structural analyses of pMHC complexes before and after TCR binding, combined with biophysical analyses, revealed that although the TCR binds similarly to all complexes, the p3P modification alters the conformations of a very limited amount of specific MHC and peptide residues, facilitating efficient TCR recognition. This approach can be easily introduced in peptides restricted to other MHC alleles, and can be combined with currently available and future vaccination protocols in order to prevent viral immune escape.Author SummaryViral escape mutagenesis correlates often with disease progression and represents a major hurdle for vaccination-based therapies. Here, we have designed and developed a novel generation of altered epitopes that re-establish and enhance significantly CD8+ T cell recognition of a naturally occurring viral immune escape variant. Biophysical and structural analyses provide a clear understanding of the molecular mechanisms underlying this reestablished recognition. We believe that this approach can be implemented to currently available or novel vaccination approaches to efficiently restore T cell recognition of virus escape variants to control disease progression.

scholarly journals Unexpected T-cell recognition of an altered peptide ligand is driven by reversed thermodynamics

2012 ◽  
Vol 42 (11) ◽  
pp. 2990-3000 ◽  
Author(s):  
Eva B. Allerbring ◽  
Adil D. Duru ◽  
Hannes Uchtenhagen ◽  
Chaithanya Madhurantakam ◽  
Markus B. Tomek ◽  
...  
Keyword(s):  
T Cell ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Cell Recognition ◽  
T Cell Recognition

MHC-peptide ligand interactions establish a functional threshold for antigen-specific T cell recognition

1999 ◽  
Vol 60 (7) ◽  
pp. 608-618 ◽  
Author(s):  
Sandra Reichstetter ◽  
William W Kwok ◽  
Sharon Kochik ◽  
David M Koelle ◽  
Jon S Beaty ◽  
...  
Keyword(s):  
T Cell ◽  
Peptide Ligand ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Ligand Interactions

scholarly journals T-Cell Tolerance for Variability in an HLA Class I-Presented Influenza A Virus Epitope

2009 ◽  
Vol 83 (18) ◽  
pp. 9206-9214 ◽  
Author(s):  
Angela Wahl ◽  
William McCoy ◽  
Fredda Schafer ◽  
Wilfried Bardet ◽  
Rico Buchli ◽  
...  
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Escape ◽  
Class I ◽  
Immune Recognition ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
The Impact

ABSTRACT To escape immune recognition, viruses acquire amino acid substitutions in class I human leukocyte antigen (HLA)-presented cytotoxic T-lymphocyte (CTL) epitopes. Such viral escape mutations may (i) prevent peptide processing, (ii) diminish class I HLA binding, or (iii) alter T-cell recognition. Because residues 418 to 426 of the hypervariable influenza A virus nucleoprotein (NP418-426) epitope are consistently bound by class I HLA and presented to CTL, we assessed the impact that intraepitope sequence variability has upon T-cell recognition. CTL elicited by intranasal influenza virus infection were tested for their cross-recognition of 20 natural NP418-426 epitope variants. Six of the variant epitopes, of both H1N1 and H3N2 origin, were cross-recognized by CTL while the remaining NP418-426 epitope variants escaped targeting. A pattern emerged whereby variability at position 5 (P5) within the epitope reduced T-cell recognition, changes at P4 or P6 enabled CTL escape, and a mutation at P8 enhanced T-cell recognition. These data demonstrate that substitutions at P4 and/or P6 facilitate influenza virus escape from T-cell recognition and provide a model for the number, nature, and location of viral mutations that influence T-cell cross-recognition.

scholarly journals Epigenetic reprogramming of tumor cell–intrinsic STING function sculpts antigenicity and T cell recognition of melanoma

2021 ◽  
Vol 118 (15) ◽  
pp. e2013598118
Author(s):  
Rana Falahat ◽  
Anders Berglund ◽  
Ryan M. Putney ◽  
Patricio Perez-Villarroel ◽  
Shota Aoyama ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cell ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Immune Escape ◽  
Type I ◽  
Cell Recognition ◽  
Melanoma Tumor ◽  
T Cell Recognition ◽  
Melanoma Cell Lines

Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell–based immunotherapies. Evidence suggests that activation of stimulator of interferon genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear. In this study, we asked whether this suppression is, in part, epigenetically regulated and whether it is indeed a driver of melanoma resistance to T cell–based immunotherapies. Using genome-wide DNA methylation profiling, we show that promoter hypermethylation of cGAS and STING genes mediates their coordinated transcriptional silencing and contributes to the widespread impairment of the STING signaling function in clinically-relevant human melanomas and melanoma cell lines. This suppression is reversible through pharmacologic inhibition of DNA methylation, which can reinstate functional STING signaling in at least half of the examined cell lines. Using a series of T cell recognition assays with HLA-matched human melanoma tumor-infiltrating lymphocytes (TIL), we further show that demethylation-mediated restoration of STING signaling in STING-defective melanoma cell lines can improve their antigenicity through the up-regulation of MHC class I molecules and thereby enhance their recognition and killing by cytotoxic T cells. These findings not only elucidate the contribution of epigenetic processes and specifically DNA methylation in melanoma-intrinsic STING signaling impairment but also highlight their functional significance in mediating tumor-immune evasion and resistance to T cell–based immunotherapies.

scholarly journals Host HLA B*Allele-Associated Multi-Clade Gag T-Cell Recognition Correlates with Slow HIV-1 Disease Progression in Antiretroviral Therapy-Naïve Ugandans

PLoS ONE ◽  
2009 ◽  
Vol 4 (1) ◽  
pp. e4188 ◽  
Author(s):  
Jennifer Serwanga ◽  
Leigh Anne Shafer ◽  
Edward Pimego ◽  
Betty Auma ◽  
Christine Watera ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
Disease Progression ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Hiv 1

scholarly journals Genetic analysis of host–parasite coevolution in human malaria

1997 ◽  
Vol 352 (1359) ◽  
pp. 1317-1325 ◽  
Author(s):  
Adrian V. S. Hill ◽  
Annette Jepson ◽  
Magdalena Plebanski ◽  
Sarah C. Gilbert
Keyword(s):  
T Cell ◽  
Viral Infections ◽  
Immune Escape ◽  
Natural Populations ◽  
Cell Epitope ◽  
T Cell Response ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Mhc Genes ◽  
Host Parasite

Recent twin studies of clinical malaria and immune responses to malaria antigens have underscored the importance of both MHC and non–MHC genes in determining variable susceptibility and immune responsiveness. By using a combination of whole genome genetic linkage studies of families and candidate gene analysis, non–MHC genes are being mapped and identified. HLA genotype was found to affect susceptibility to severe malaria in a large study of West African children. T lymphocytes that may mediate such resistance have been identified and their target antigens and epitopes characterized. Some of these epitopes show substantial polymorphism, which appears to result from immune selection pressure. Natural variant epitopes have been found to escape T–cell recognition in cytolytic and other T–cell assays. More recently a novel immune escape mechanism has been described in viral infections, altered peptide ligand antagonism, whereby variants of a T–cell epitope can downregulate or ablate a T cell response to the index peptide. The likely implications of such immune escape mechanisms for the population structure of malaria parasites, for HLA associations with malaria infection and disease, and for the design of new malaria vaccines, are discussed. The evolutionary consequences of such molecular interactions can be assessed by using mathematical models that capture the dynamic interplay of variable host and parasite molecules. Combined genetic, immunological and mathematical analysis of host and parasite variants in natural populations can identify some mechanisms driving host–parasite coevolution.

scholarly journals A Naturally Selected Dimorphism within the HLA-B44 Supertype Alters Class I Structure, Peptide Repertoire, and T Cell Recognition

2003 ◽  
Vol 198 (5) ◽  
pp. 679-691 ◽  
Author(s):  
Whitney A. Macdonald ◽  
Anthony W. Purcell ◽  
Nicole A. Mifsud ◽  
Lauren K. Ely ◽  
David S. Williams ◽  
...  
Keyword(s):  
T Cell ◽  
Peptide Ligands ◽  
Class I ◽  
Human Populations ◽  
Cell Recognition ◽  
Differential Impact ◽  
Cell Repertoire ◽  
T Cell Recognition ◽  
Naturally Occurring ◽  
Selection Of

HLA-B*4402 and B*4403 are naturally occurring MHC class I alleles that are both found at a high frequency in all human populations, and yet they only differ by one residue on the α2 helix (B*4402 Asp156→B*4403 Leu156). CTLs discriminate between HLA-B*4402 and B*4403, and these allotypes stimulate strong mutual allogeneic responses reflecting their known barrier to hemopoeitic stem cell transplantation. Although HLA-B*4402 and B*4403 share >95% of their peptide repertoire, B*4403 presents more unique peptides than B*4402, consistent with the stronger T cell alloreactivity observed toward B*4403 compared with B*4402. Crystal structures of B*4402 and B*4403 show how the polymorphism at position 156 is completely buried and yet alters both the peptide and the heavy chain conformation, relaxing ligand selection by B*4403 compared with B*4402. Thus, the polymorphism between HLA-B*4402 and B*4403 modifies both peptide repertoire and T cell recognition, and is reflected in the paradoxically powerful alloreactivity that occurs across this “minimal” mismatch. The findings suggest that these closely related class I genes are maintained in diverse human populations through their differential impact on the selection of peptide ligands and the T cell repertoire.

608 Immunodominant listeria epitopes compete with vaccine-directed cd8+ t-cell responses rescued by peptide-MHC stabilizing modifications

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A644-A644
Author(s):  
John Flickinger ◽  
Jagmohan Singh ◽  
Yanki Yarman ◽  
Robert Carlson ◽  
Scott Waldman ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
T Cell ◽  
Cell Line ◽  
Mhc Class I ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Class I ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Cell Responses

BackgroundThe Gram-positive bacterium Listeria monocytogenes (Lm) is a promising vector for cancer immunotherapy due to its ability to directly infect antigen-presenting cells, induce potent CD8+ T-cell immunity, and remodel immunosuppressive tumor microenvironments.1 Recent clinical trials have demonstrated safety and immunogenicity of Lm-based cancer vaccines in lung, cervical, pancreatic, and other cancers. In colorectal cancer, the transmembrane receptor guanylyl cyclase C (GUCY2C) is an emerging target for immunotherapy.2 Here, we examined the immunogenicity of a recombinant strain of Listeria monocytogenes secreting GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination induced robust Lm-specific CD8+ T-cell immunity but failed to prime GUCY2C-specific CD8+ T-cell responses. These studies explore the hypothesis that immunodominant Lm antigens suppress primary immunity to subdominant GUCY2C epitopes in Lm-GUCY2CMethodsLm-GUCY2C expresses the extracellular domain of mouse GUCY2C23-429 downstream of an ActA promoter integrated into the genome of the live, attenuated delta actA delta inlB Lm strain. Altered peptide ligands were designed based on NetMHCpan 4.0 peptide-MHC binding algorithms and similarly cloned into Lm. Peptide-MHC class I complex stability was quantified by FACS-based surface peptide-MHC dissociation on the TAP-deficient cell line, RMA-S H-2Kd.3In vivo efficacy studies employed IFNγ-ELISpot quantification of T-cell responses and tumor challenge studies with the CT26 colorectal cancer cell line. Adenovirus expressing GUCY2C was used as a positive control.2 4ResultsLm-GUCY2C vaccination of BALB/c mice generated Lm-specific CD8+ T-cell responses but an absence of GUCY2C-specific immunity. Peptide-MHC stability studies revealed poor stability of the dominant GUCY2C254-262 epitope complexed with H-2Kd compared to H-2Kd-restricted Lm epitopes derived from the LLO and p60 Lm antigens. Mutation of the GUCY2C254-262 peptide at critical anchoring residues for binding H-2Kd revealed that the altered peptide ligand with an F255Y mutation significantly improved the stability of the GUCY2C254-262-H-2Kd complex. Similarly, vaccination of mice with recombinant Lm-GUCY2C expressing the altered peptide ligand (Lm-GUCY2CF255Y) restored GUCY2C immunogenicity and antitumor immunity.ConclusionsImmunodominant Lm antigens may interfere with immune responses directed to the vaccine target antigen GUCY2C by competing with GUCY2C epitope for MHC class I binding and presentation. Moreover, use of a substituted GUCY2C -peptide ligand with enhanced peptide-MHC class I stability restored GUCY2C-specific immunity in the context of Lm-GUCY2C, an approach that can be translated to patients. Importantly, these studies also suggest that ongoing Lm-based vaccine development programs targeting a variety of antigens in other cancer types may be similarly limited by the immunodominance of Lm epitopes.AcknowledgementsThe authors thank Dr. Peter Lauer for providing the pPL2 integration vector used in cloning Lm-GUCY2C and Dr. Sean Murphy for providing the RMA-S H-2Kd cell line.Ethics ApprovalStudies were approved by the Thomas Jefferson University IACUC (Protocol # 01956).ReferencesFlickinger JC, Rodeck U, Snook AE. Listeria monocytogenes as a Vector for Cancer Immunotherapy: Current Understanding and Progress. Vaccines (Basel) 2018;6. doi:10.3390/vaccines6030048.Snook AE, Baybutt TR, Xiang B, Abraham TS, Flickinger JC, Hyslop T, et al. Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients. J Immunother Cancer 2019;7:104. doi:10.1186/s40425-019-0576-2.Müllbacher A, Lobigs M, Kos FJ, Langman R. Alloreactive cytotoxic T-cell function, peptide nonspecific. Scand J Immunol 1999;49:563–9.Flickinger J. JC, Singh J, Carlson R, Leong E, Baybutt T, Barton J, et al. Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity. J Immunother Cancer 2020.

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