Multiple DNA and protein sequence alignments have been constructed for the human T-cell receptor alpha/delta, beta, and gamma (TCRA/D, B, and G) variable (V) gene segments. The traditional classification into subfamilies was confirmed using a much larger pool of sequences. For each sequence, a name was derived which complies with the standard nomenclature. The traditional numbering of V gene segments in the order of their discovery was continued and changed when in conflict with names of other segments. By discriminating between alleles at the same locus versus genes from different loci, we were able to reduce the number of more than 150 different TCRBV sequences in the database to a repertoire of only 47 functional TCRBV gene segments. An extension of this analysis to the over 100 TCRAV sequences results in a predicted repertoire of 42 functional TCRAV gene segments. Our alignment revealed two residues that distinguish between the highly homologous V delta and V alpha, one at a site that in VH contacts the constant region, the other at the interface between immunoglobulin VH and VL. This site may be responsible for restricted pairing between certain V delta and V gamma chains. On the other hand, V beta and V gamma appear to be related by the fact that their CDR2 length is increased by four residues as compared with that of V alpha/delta peptides.

Human T-cell receptor variable gene segment families.

Development of thymocytes involves two distinct outcomes resulting from superficially similar events. Recognition by thymocytes of major histocompatibility complex (MHC) proteins plus peptides leads to their rescue from apoptosis (positive selection), and recognition of antigenic peptide induces cell death (negative selection). Antigen analogues, and sometimes low concentrations of antigenic peptide, induce positive selection; such analogues are often antagonists of mature T-cell clones. Various models seek to explain how recognition of different peptide/MHC complexes leads to such different outcomes: quantitative models relate response to the affinity, avidity or kinetics of T-cell-antigen receptor (TCR) binding, whereas qualitative models require conformational or spatial changes in the TCR or associated molecules to modulate signal transduction. We have used surface plasmon resonance to measure the kinetics of TCR interactions with positively and negatively selecting ligands to distinguish between these models, and find that affinity correlates to the outcome of selection. A 'window' of affinity resulting in positive selection extends over a 1-log range starting threefold below the affinity for negative selection.

T-cell-receptor affinity and thymocyte positive selection

We describe here a new subset of T cells, found in humans, mice, and cattle. These cells bear a canonical T cell receptor (TCR) α chain containing hAV7S2 and AJ33 in humans and the homologous AV19-AJ33 in mice and cattle with a CDR3 of constant length. These T cells are CD4−CD8− double-negative (DN) T cells in the three species and also CD8αα in humans. In humans, their frequency was ∼1/10 in DN, 1/50 in CD8α+, and 1/6,000 in CD4+ lymphocytes, and they display an activated/memory phenotype (CD45RAloCD45RO+). They preferentially use hBV2S1 and hBV13 segments and have an oligoclonal Vβ repertoire suggesting peripheral expansions. These cells were present in major histocompatibility complex (MHC) class II– and transporter associated with antigen processing (TAP)-deficient humans and mice and also in classical MHC class I– and CD1-deficient mice but were absent from β2-microglobulin–deficient mice, indicating their probable selection by a nonclassical MHC class Ib molecule distinct from CD1. The conservation between mammalian species, the abundance, and the unique selection pattern suggest an important role for cells using this novel canonical TCR α chain.

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An invariant T cell receptor α chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted α/β T cell subpopulation in mammals

▪ Abstract Pseudogenes have been defined as nonfunctional sequences of genomic DNA originally derived from functional genes. It is therefore assumed that all pseudogene mutations are selectively neutral and have equal probability to become fixed in the population. Rather, pseudogenes that have been suitably investigated often exhibit functional roles, such as gene expression, gene regulation, generation of genetic (antibody, antigenic, and other) diversity. Pseudogenes are involved in gene conversion or recombination with functional genes. Pseudogenes exhibit evolutionary conservation of gene sequence, reduced nucleotide variability, excess synonymous over nonsynonymous nucleotide polymorphism, and other features that are expected in genes or DNA sequences that have functional roles. We first review the Drosophila literature and then extend the discussion to the various functional features identified in the pseudogenes of other organisms. A pseudogene that has arisen by duplication or retroposition may, a...

https://apologetyka.com/ptkr/groups/ptkrmember/inne/2003/Pseudogenes%20Are%20they%20junk...,%20caly%20tekst%20Balakirev.pdf

Pseudogenes: are they "junk" or functional DNA?

The expansion and contraction of specific helper T cells in the draining lymph nodes of normal mice after injection with antigen was followed. T cell receptors from purified primary and memory responder cells had highly restricted junctional regions, indicating antigen-driven selection. Selection for homogeneity in the length of the third complementarity-determining region (CDR3) occurs before selection for some of the characteristic amino acids, indicating the importance of this parameter in T cell receptor recognition. Ultimately, particular T cell receptor sequences come to predominate in the secondary response and others disappear, showing the selective preservation or expansion of specific T cell clones.

https://science.sciencemag.org/content/sci/268/5207/106.full.pdf

Chia Lam Kuo

Papers

The human T-cell receptor TCRAC/TCRDC (C alpha/C delta) region: organization, sequence, and evolution of 97.6 kb of DNA.