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Differential T-Cell Receptor Signaling: A Novel Paradigm for Thymic Selection and Lineage Commitment

DOI: 10.4236/oalib.1114914, PP. 1-25

Subject Areas: Immunology

Keywords: Differential TCR Signaling, Differential Affinity Threshold, Repertoire Diversity, Segregated Peptide Recognition, Four Checkpoints in Thymic Selection, Equivalence of Self-Recognition

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Abstract

The canonical affinity-threshold model of thymic T-cell selection posits that thymocyte fate is determined by TCR-pMHC integrated affinity. However, this model fails to explain high thymocyte deletion rates, diverse TCR affinities in mature repertoires, and precise CD4/CD8 lineage commitment mechanisms. We propose a novel Differential TCR Signaling Model wherein the functional TCR signal is a relative comparison: TCRβ signal strength relative to a dynamic TCRα-derived self-reference threshold (TCR = TCRβ/TCRα). This requires functional partitioning of pMHC recognition: TCRα (via VJ recombination) engages the N-terminal peptide half (Seg1) to establish a tunable self-reference, while TCRβ (via V(D)J recombination) targets the C-terminal half (Seg2) harboring antigenic information. Consequently, thymic selection expands to four distinct checkpoints aimed at achieving Equivalence of Self-Recognition (TCRα ≈ TCRβ) on self-ligands, ensuring near-zero differential signaling and stringent central tolerance. TCRα rearrangement becomes an active α-negative selection process, reducing TCRα affinity to balance fixed TCRβ signals. The kinetics of achieving equivalence deterministically dictate lineage fate: strong initial TCRβ signals promote rapid balancing and CD4 commitment, while weaker signals require prolonged tuning and often coreceptor reversal (CD4 → CD8) for MHC I balance, leading to CD8 commitment. This model redefines T-cell development as active, quantitative self-recognition calibration, providing a unified explanation for thymic attrition, repertoire diversity, and lineage choice, and establishing a quantifiable 3:1 self-to-antigen recognition confidence ratio fundamental to immune discrimination.

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Maassoom, Y. A. (2026). Differential T-Cell Receptor Signaling: A Novel Paradigm for Thymic Selection and Lineage Commitment. Open Access Library Journal, 13, e14914. doi: http://dx.doi.org/10.4236/oalib.1114914.

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