How the thymus designs antigen-specific and self-tolerant T cell receptor sequences

Abstract

T lymphocytes (T cells) orchestrate adaptive immune responses that clear pathogens from infected hosts. T cells recognize short peptides (p) derived from antigenic proteins bound to protein products of the MHC genes. Recognition occurs when T cell receptor (TCR) proteins expressed on T cells bind sufficiently strongly to antigen-derived pMHC complexes on the surface of antigenpresenting cells. A diverse repertoire of self-pMHC-tolerant TCR sequences is shaped during development of T cells in the thymus by processes called positive and negative selection. Combining computational models and analysis of experimental data, we parsed the contributions of positive and negative selection to the design of TCR sequences that recognize antigenic peptides with specificity, yet also exhibit cross-reactivity. A dominant role for negative selection in mediating antigen specificity of mature T cells and a molecular mechanism for TCR recognition of antigen are described.statistical mechanics ͉ T cell antigen specificity ͉ thymic selection B ecause T cell receptor (TCR) genes undergo stochastic somatic rearrangement, most T cells express a distinct TCR, thereby enabling the T cell population to recognize many different antigenic short peptide (p)MHC complexes. TCR recognition of pMHC is both specific and degenerate. It is specific, because if a TCR recognizes a particular pMHC complex, most mutations to the peptide amino acids abrogate recognition (1, 2). It is degenerate because a given TCR can interact productively with several antigenic peptides (3). pMHC complexes where the peptide is derived from the cell's own proteins are also displayed on antigenpresenting cell (APC) surfaces. TCRs are self-tolerant because they bind weakly to these ''self''-pMHC complexes, thereby avoiding frequent autoimmune responses.The diverse, specific/degenerate, and self-tolerant T cell repertoire is designed during T cell development in the thymus (4-8). Immature T cells (thymocytes) interact with a variety of self-pMHC molecules expressed on the surface of thymic epithelial cells as well as hematopoietically derived macrophages and dendritic cells. Thymocytes expressing a TCR that binds with high affinity to any self-pMHC molecule are deleted in the thymus (a process called negative selection). However, a thymocyte's TCR must also bind sufficiently strongly to at least one type of self pMHC complex to receive survival signals and emigrate from the thymus (a process called positive selection).Signaling events, gene transcription programs, and cell migration during T cell development in the thymus have been studied extensively (4-14). Despite important advances, how interactions with self-pMHC complexes in the thymus shape the peptidebinding properties of selected TCR amino acid sequences such that mature T cells exhibit their special properties is poorly understood.Recent experiments carried out by Huseby et al.(1, 2) provided important clues in this regard. These experiments determined differences in how T cells interact with foreign (antigenic...

Evolving concepts of specificity in immune reactions

“…Another mechanistic view of the specificity/degeneracy enigma stems from considerations of the statistical properties of the TCR repertoire rather than analyses of the detailed interactions of particular TCR-pMHC pairs. Because the TCR diversity attributable to gene rearrangements is enormous and their selection during development in the thymus varies among individuals, such a statistical view may provide general insights applicable to many TCRs (104).…”

“…Using computational methods rooted in statistical physics, independent of the choice of parameters used to estimate TCR-pMHC binding free energies, it was predicted that T cells whose TCR peptide contact residues are composed of amino acids that interact strongly with other amino acids (e.g., charged, strongly hydrophobic, with very flexible side chains) are more likely to be eliminated by negative selection in a thymus that expresses a great diversity of self-pMHCs (104). Analysis of available TCR-pMHC crystal structures showed that peptide-contact residues of TCRs are indeed enriched with those amino acids that are determined by bioinformatic studies to interact weakly with other amino acids (108).…”

Nonspecific binding limits the number of proteins in a cell and shapes their interaction networks

“…To calculate interaction energies, we use the experimentally derived Miyazawa-Jernigan (MJ) contact potentials, tuned for protein binding (25,26). Previous studies of immune recognition used similar energy functions and selection strategies (19,27). In the optimization, we require the overall amino acid composition to be consistent with experimental observation (28) (see Methods).…”

Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1

“…Subsequent work by Smith et al established parameters for a shape space model using immunological data (18) and later adapted it for use in a stochastic simulation of affinity maturation to accurately predict the efficacy of repeated influenza vaccinations from clinical data (19). Beyond studying affinity maturation, computational immunology approaches been used to study T cell activation (20,21) and specificity (22), viral infection and adaptation (23)(24)(25)(26)(27), and innate immunity (28).…”