Immune repertoire analysis

Image Bcell_Tcell
Figure 7.1: T and B cell receptors structure. Each pair of chains forms an antigen binding site that binds to specific antigens.

T and B cells form our acquired immune response. They both contain highly variable receptors (see figure 7.1) with binding sites that recognize antigens.

T and B cell receptors (TCR and BCR, respectively) are composed of multiple polypeptide chains: TCRs contain one pair, while BCRs contain two copies of a pair:

TCR: $\alpha$ (TRA) and $\beta$ (TRB), or $\gamma$ (TRG) and $\delta$ (TRD).
BCR: light and heavy. There are two types of light chains in humans: $\kappa$ (IGK) and $\lambda$ (IGL), while other animals also contain other types of light chains. Once set, the light chain class remains fixed for the life of the B cell. There are five types of heavy chains (IGH) for mammals: $\gamma$ , $\delta$ , $\alpha$ , $\mu$ and $\eta$ , defining the class of the receptor.

The chains are encoded by genes that undergo somatic recombination. During this process, gene segments are joined with random nucleotides at the junction sites. There are two types of recombination (see figure 7.2):

VJ recombination, where one V (variable) gene segment is joined to a J (joining) gene segment;
VDJ recombination, where a D (diversity) gene segment is added between the V and J gene segments.

Image DNA_RNA
Figure 7.2: VDJ recombination brings together a V, D, J and C gene segment.

For both types of recombination, a C (constant) gene segment is also added following the J segment.

The TRA and TRG chains are the result of VJ recombination, while the TRB and TRD chains are the result of VDJ recombination. The V, D, J and C gene segments are specific for each TCR chain type.

BCR light chains are the result of VJ recombination, while BCR heavy chains are the result of VDJ recombination. BCR heavy chains have three to four C gene segments. The V, D, J and C gene segments are specific for each BCR light chain type, while they are shared by the BCR heavy chains.

Each chain contains three "complementary-determining regions" (CDRs) (figure 7.2) which form loops in the antigen binding sites. The V(D)J recombination junction is located in the third CDR (CDR3). Due to inclusion of random nucleotides at the junctions between segments, the CDR3 is the most diverse among the three CDRs. Its beginning and end are marked by a conserved cysteine (C) and phenylalanine/tryptophan (F/W) amino-acid in the V and J segments, respectively.

Biomedical Genomics Analysis offers tools to clonotype reads and characterize the T or B cell receptor repertoire (Immune Repertoire Analysis), filter the repertoires (Filter Immune Repertoire) and compare them (Compare Immune Repertoires). Here, clonotyping a read consists of identifying which V, D, J and C segments from the reference data (see Immune Repertoire Analysis) are used, and extracting the CDR3 region found between the conserved amino acids.

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Immune repertoire analysis