Identification of a potent regulatory T cell epitope in factor V that modulates CD4+ and CD8+ memory T cell responses

Groot, Anne S. De; Rosenberg, Amy S.; Miah, S. M. Shahjahan; Skowron, Gail; Roberts, Brian; Lélias, Sandra; Terry, Frances; Martin, William

doi:10.1016/j.clim.2020.108661

Cited by 17 publications

(34 citation statements)

References 50 publications

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“…The findings of this study suggested that the early administration of CD91 derived Treg epitope (SGS peptide) induces the expansion of Tregs and may prevent abortions in an abortion-prone mouse model. The identified SGS peptide meets the criteria of a tregitope, as its sequence is present in prevalent human proteins, conservative across many species, and can bind to the human leukocyte antigen-DR isotype (HLA-DR) [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

CD91 Derived Treg Epitope Modulates Regulatory T Lymphocyte Response, Regulates Expression of Costimulatory Molecules on Antigen-Presenting Cells, and Rescues Pregnancy in Mouse Pregnancy Loss Model

Kędzierska

Lorek

Sławek

et al. 2021

IJMS

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The loss of immune tolerance to fetal antigens may result in reproductive failure. The downregulated number and activity of T regulatory lymphocytes, which are critical for the establishment of immune tolerance to fetal antigens, during pregnancy may lead to miscarriage. The adoptive transfer of Tregs prevents fetal loss in abortion-prone mice. Recently, we demonstrated that the administration of tregitopes, which are short peptides found in human and mouse immunoglobulins (IgGs), decreased the incidence of abortions in female CBA/J mice mated with DBA/2J mice. Here, two non-IgG source peptides (SGS and LKD) that can potentially bind to the major histocompatibility complex II (MHC II) with high affinity and induce Treg expansion were designed in silico. The immune dysregulation-induced pregnancy failure mouse model was used to evaluate the effect of SGS and LKD on immune response and pregnancy outcome. The fetal death rate in the SGS-treated group was lower than that in the phosphate-buffered saline-treated group. SGS and LKD upregulated the splenic pool of Tregs and modulated the T-helper cell (Th1)/Th2-related cytokine response at the preimplantation stage. Additionally, SGS and LKD downregulated the expression of CD80 and MHC class II molecules in splenic CD11c+ antigen-presenting cells. Thus, SGS treatment can result in beneficial pregnancy outcomes. Additionally, SGS peptide-mediated immunomodulation can be a potential therapeutic strategy for immune dysregulation-induced pregnancy failure.

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Section: Introductionmentioning

confidence: 99%

CD91 Derived Treg Epitope Modulates Regulatory T Lymphocyte Response, Regulates Expression of Costimulatory Molecules on Antigen-Presenting Cells, and Rescues Pregnancy in Mouse Pregnancy Loss Model

Kędzierska

Lorek

Sławek

et al. 2021

IJMS

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“…This improved version that integrated putatively tolerated and tolerogenic epitopes predicted ADA status accurately for 64% of subjects. To explore the interesting hypothesis that these epitopes might down-modulate T effector responses to ERT we used a validated in vitro T cell assay (The Tetanus Toxoid Bystander Suppression Assay (TTBSA) ( 27 ) to examine their potential regulatory effects, using blood from naïve donors. We confirmed that four of the 21 GAA epitopes tested in vitro appear to be significantly immunomodulatory.…”

Section: Discussionmentioning

confidence: 99%

“…The discovery of Treg epitopes in self proteins has implications for protein therapeutics and may help explain why some subjects unexpectedly develop tolerance to ERT or blood factor therapy. For example, we have identified a Treg epitope in Factor V that may induce tolerance to Factor VIII in certain hemophilia A subjects ( 27 ). The potential for human proteins to have internal Treg epitopes may transform the prediction of ADA development for Pompe patients and has important implications for other protein-based replacement therapies ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

“…The positive (regulatory T cell epitope) control for this assay was a Treg epitope similar to the previously identified Tregitopes ( 26 ), FV621. This control peptide is a Factor V peptide that modulates CD4+ memory T cell responses and induces bystander suppression of T effector immune response in vitro in a standardized Tetanus Toxin Bystander Suppression Assay (TTBSA) ( 27 ).…”

Section: Methodsmentioning

confidence: 99%

“…The TTBSA measures the inhibitory capacity of potential regulatory peptides on the recall response of human CD4 T cells to the tetanus toxoid (TT) antigen was adapted for validation of Treg epitopes and previously described ( 27 , 31 ). TT vaccination is a routine, nearly universal immunization, resulting in memory T cell responses that persist for many years ( 32 ).…”

Section: Methodsmentioning

confidence: 99%

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Immune Tolerance-Adjusted Personalized Immunogenicity Prediction for Pompe Disease

et al. 2021

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Infantile-onset Pompe disease (IOPD) is a glycogen storage disease caused by a deficiency of acid alpha-glucosidase (GAA). Treatment with recombinant human GAA (rhGAA, alglucosidase alfa) enzyme replacement therapy (ERT) significantly improves clinical outcomes; however, many IOPD children treated with rhGAA develop anti-drug antibodies (ADA) that render the therapy ineffective. Antibodies to rhGAA are driven by T cell responses to sequences in rhGAA that differ from the individuals’ native GAA (nGAA). The goal of this study was to develop a tool for personalized immunogenicity risk assessment (PIMA) that quantifies T cell epitopes that differ between nGAA and rhGAA using information about an individual’s native GAA gene and their HLA DR haplotype, and to use this information to predict the risk of developing ADA. Four versions of PIMA have been developed. They use EpiMatrix, a computational tool for T cell epitope identification, combined with an HLA-restricted epitope-specific scoring feature (iTEM), to assess ADA risk. One version of PIMA also integrates JanusMatrix, a Treg epitope prediction tool to identify putative immunomodulatory (regulatory) T cell epitopes in self-proteins. Using the JanusMatrix-adjusted version of PIMA in a logistic regression model with data from 48 cross-reactive immunological material (CRIM)-positive IOPD subjects, those with scores greater than 10 were 4-fold more likely to develop ADA (p<0.03) than those that had scores less than 10. We also confirmed the hypothesis that some GAA epitopes are immunomodulatory. Twenty-one epitopes were tested, of which four were determined to have an immunomodulatory effect on T effector response in vitro. The implementation of PIMA V3J on a secure-access website would allow clinicians to input the individual HLA DR haplotype of their IOPD patient and the GAA pathogenic variants associated with each GAA allele to calculate the patient’s relative risk of developing ADA, enhancing clinical decision-making prior to initiating treatment with ERT. A better understanding of immunogenicity risk will allow the implementation of targeted immunomodulatory approaches in ERT-naïve settings, especially in CRIM-positive patients, which may in turn improve the overall clinical outcomes by minimizing the development of ADA. The PIMA approach may also be useful for other types of enzyme or factor replacement therapies.

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Restoring immune balance with Tregitopes: A new approach to treating immunological disorders

Javidan,

Amiri,

Koohi

et al. 2024

Biomedicine & Pharmacotherapy

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Identification of a potent regulatory T cell epitope in factor V that modulates CD4+ and CD8+ memory T cell responses

Cited by 17 publications

References 50 publications

CD91 Derived Treg Epitope Modulates Regulatory T Lymphocyte Response, Regulates Expression of Costimulatory Molecules on Antigen-Presenting Cells, and Rescues Pregnancy in Mouse Pregnancy Loss Model

CD91 Derived Treg Epitope Modulates Regulatory T Lymphocyte Response, Regulates Expression of Costimulatory Molecules on Antigen-Presenting Cells, and Rescues Pregnancy in Mouse Pregnancy Loss Model

Immune Tolerance-Adjusted Personalized Immunogenicity Prediction for Pompe Disease

Restoring immune balance with Tregitopes: A new approach to treating immunological disorders

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