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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

Diversity of Antigen Receptors

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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.
Complete Antigens
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Antigen Processing Pathways01:31

Antigen Processing Pathways

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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

B Cell Activation and Differentiation

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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 24, 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.

Research Square
|June 10, 2024
PubMed
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T cell receptor (TCR) specificity for cancer neoantigens is determined by dynamic motions within the HLA-A3 binding groove. These dynamic movements act as a gate, influencing T cell receptor binding to neoantigens versus wild-type peptides.

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Area of Science:

  • Immunology
  • Structural Biology
  • Computational Biology

Background:

  • T cell receptor (TCR) cross-reactivity presents a challenge in understanding T cell specificity.
  • Static protein structures often fail to explain the nuanced discrimination observed in T cell recognition.
  • Understanding TCR recognition mechanisms is crucial for developing effective cancer immunotherapies.

Purpose of the Study:

  • To elucidate the dynamic mechanisms underlying T cell receptor (TCR) specificity for a specific cancer neoantigen.
  • To investigate how peptide variations within the HLA-A3 binding groove influence TCR recognition.
  • To reveal the role of HLA-A3 peptide binding groove dynamics in discriminating between mutant and wild-type peptides.

Main Methods:

  • Analysis of dynamic motions within the HLA-A3 binding groove using computational modeling.
  • Investigation of peptide anchor residue effects on HLA-A3 conformation.
  • Characterization of T cell receptor (TCR) binding facilitation through dynamic allosteric mechanisms.

Main Results:

  • TCR discrimination between a mutant PIK3CA neoantigen and its wild-type counterpart is driven by dynamic motions in the HLA-A3 binding groove.
  • Peptide anchor identity modulates HLA-A3 groove dynamics, creating a 'dynamic gate' that affects TCR binding.
  • The neoantigen's structure allows for a conformational change facilitating TCR binding, unlike the wild-type peptide.

Conclusions:

  • TCR specificity for cancer neoantigens is governed by dynamic and allosteric interactions of peptide/MHC-I complexes.
  • The findings provide a novel mechanism for understanding T cell specificity in cancer.
  • This research has implications for designing targeted immunotherapies based on dynamic TCR-peptide-MHC interactions.