Killer Cell Immunoglobulin Receptors and T Cell Receptors Bind Peptide-Major Histocompatibility Complex Class I with Distinct Thermodynamic and Kinetic Properties

Background: Globally, the recent outbreak of Zika virus (ZIKV) in Brazil, Asia Pacific, and other countries highlighted the unmet medical needs. Currently, there are neither effective vaccines nor therapeutics available to prevent or treat ZIKV infection. Objective: In this study, we aimed to design an epitope-based vaccine for ZIKV using an in silico approach to predict and analyze B- and T-cell epitopes. Methods: The prediction of the most antigenic epitopes has targeted the capsid and the envelope proteins as well as nonstructural proteins NS5 and NS3 using immune-informatics tools PROTPARAM, CFSSP, PSIPRED, and Vaxijen v2.0. B and T-cell epitopes were predicted using ABCpred, IEDB, TepiTool, and their toxicity were evaluated using ToxinPred. The 3-dimensional epitope structures were generated by PEP-FOLD. Energy minimization was performed using Swiss-Pdb Viewer, and molecular docking was conducted using PatchDock and FireDock server. Results: As a result, we predicted 307 epitopes of MHCI (major histocompatibility complex class I) and 102 epitopes of MHCII (major histocompatibility complex class II). Based on immunogenicity and antigenicity scores, we identified the four most antigenic MHC I epitopes: MVLAILAFLR (HLA-A*68 :01), ETLHGTVTV (HLA-A*68 :02), DENHPYRTW (HLA-B*44 :02),QEGVFHTMW (HLA-B*44 :03) and TASGRVIEEW (HLA-B*58:01), and MHC II epitopes: IIKKFKKDLAAMLRI (HLA-DRB3*02 :02), ENSKMMLELDPPFGD (HLA-DRB3*01:01), HAETWFFDENHPYRT (HLA-DRB3*01:01), TDGVYRVMTRRLLGS (HLA-DRB1*11 :01), and DGCWYGMEIRPRKEP (HLA-DRB5*01:01). Conclusion : This study provides novel potential B cell and T cell epitopes to fight Zika virus infections and may prompt further development of vaccines against ZIKV and other emerging infectious diseases. However, further investigations for protective immune response by in vitro and in vivo studies to ratify the immunogenicity, safety of the predicted structure, and ultimately the vaccine properties to prevent ZIKV infections are warranted.

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Major Histocompatibility Complex Class I Molecules Modulate Activation Threshold and Early Signaling of T Cell Antigen Receptor–γ/δ Stimulated by Nonpeptidic Ligands

Journal of Experimental Medicine ◽

10.1084/jem.186.10.1769 ◽

1997 ◽

Vol 186 (10) ◽

pp. 1769-1774 ◽

Cited By ~ 68

Author(s):

Ilaria Carena ◽

Abdijapar Shamshiev ◽

Alena Donda ◽

Marco Colonna ◽

Gennaro De Libero

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

Major Histocompatibility Complex Class ◽

Class I ◽

Complex Class ◽

Inhibitory Receptors ◽

Activation Threshold ◽

Cell Antigen Receptor ◽

Cell Antigen ◽

Histocompatibility Complex

Killer cell inhibitory receptors and CD94-NKG2-A/B heterodimers are major histocompatibility complex class I–specific inhibitory receptors expressed by natural killer cells, T cell antigen receptor (TCR)-γ/δ cells, and a subset of TCR-α/β cells. We studied the functional interaction between TCR-γ/δ and CD94, this inhibitory receptor being expressed on the majority of γ/δ T cells. When engaged by human histocompatibility leukocyte antigen class I molecules, CD94 downmodulates activation of human TCR-γ/δ by phosphorylated ligands. CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of antigen. CD94 engagement has major effects on TCR signaling cascade. It facilitates recruitment of SHP-1 phosphatase to TCR–CD3 complex and affects phosphorylation of Lck and ZAP-70 kinase, but not of CD3 ζ chain upon TCR triggering. These events may cause abortion of proximal TCR-mediated signaling and set a higher TCR activation threshold.

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