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Related Concept Videos

T Cell Activation and Clonal Selection01:22

T Cell Activation and Clonal Selection

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T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
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Diversity of Antigen Receptors01:28

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Antigen receptors are essential components of the immune system crucial in defending the body against foreign invaders. These receptors are present on the surface of B and T cells, enabling them to recognize antigens and mount an appropriate immune response.
Before encountering any antigen, lymphocytes express these receptors. On B cells, the antigen receptor is a membrane-bound antibody molecule called BCR; on T cells, it is a T cell receptor or TCR. B and T cell receptors are composed of two...
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Antigens Involved in Adaptive Immunity01:26

Antigens Involved in Adaptive Immunity

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An antigen is any substance the immune system identifies as foreign and potentially harmful to the body, prompting an immune response. Antigens have two functional properties: immunogenicity and reactivity. Immunogenicity is the ability of an antigen to stimulate a specific immune response. At the same time, reactivity describes the antigen's ability to react with the cells and antibodies produced in response to it.
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Antigen Processing Pathways01:31

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MHC molecules are key players in the immune response, enabling T cells to recognize and respond to specific antigens. They are present on the surface of all nucleated cells in the body and are instrumental in presenting antigens to T cells and activating them. T cells recognize the MHC-antigen complex and initiate an immune response. MHC class I and MHC class II are two main types of MHC molecules, each associated with a distinct antigen processing pathway.
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B Cell Activation and Differentiation01:24

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The adaptive immune response, a sophisticated defense mechanism, relies on the activation and differentiation of B lymphocytes, or B cells. These processes enable our bodies to mount a tailored response against specific pathogens such as bacteria, free virus particles, toxins, and parasites.
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Special Features of Adaptive Immunity01:20

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HLA micropolymorphisms confine neoantigen conformational adaptability and guide T cell receptor selectivity.

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Related Experiment Video

Updated: Jun 1, 2025

Using X-ray Crystallography, Biophysics, and Functional Assays to Determine the Mechanisms Governing T-cell Receptor Recognition of Cancer Antigens
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Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.

Jiaqi Ma1,2, Cory M Ayres1,2, Chad A Brambley1,2

  • 1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.

Nature Communications
|January 20, 2025
PubMed
Summary

T cell receptor (TCR) specificity for cancer neoantigens arises from dynamic motions in the HLA-A3 peptide binding groove. These motions create a gate, allowing neoantigen binding while blocking wild-type peptides.

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Area of Science:

  • Immunology
  • Structural Biology
  • Computational Biology

Background:

  • T cell receptor (TCR) recognition of antigens is crucial for adaptive immunity.
  • TCR specificity is often difficult to predict from static protein structures.
  • Antigen cross-reactivity is an inherent property of TCRs, necessitating high specificity.

Purpose of the Study:

  • To elucidate the molecular mechanism underlying TCR specificity for a neoantigen presented by HLA-A3.
  • To investigate how dynamic motions in the peptide-binding groove influence TCR-pMHC interactions.
  • To understand the structural basis for discriminating between a neoantigen and its wild-type counterpart.

Main Methods:

  • Molecular dynamics simulations of HLA-A3 presenting wild-type and neoantigen peptides.
  • Analysis of conformational changes in the HLA-A3 peptide binding groove.
  • TCR binding assays to assess specificity.

Main Results:

  • Distinct dynamic motions were observed in the HLA-A3 peptide binding groove depending on the peptide's anchor residue.
  • These motions form a dynamic gate that restricts TCR binding to the wild-type peptide.
  • The neoantigen bypasses this gate, enabling TCR engagement and a unique conformational change involving tryptophan translocation.

Conclusions:

  • TCR specificity is driven by dynamic and allosteric mechanisms within the peptide/MHC-I binding groove.
  • Peptide-induced conformational changes in MHC molecules are critical for TCR discrimination.
  • This provides a novel framework for understanding T cell recognition of cancer neoantigens.