Innate Versus Adaptive Immunity
Innate immunity provides an immediate and non-specific response to a variety of pathogens. The innate response is usually triggered when microbes are identified by receptors which recognize components that are conserved among broad groups of microorganisms. The innate immune system does not remember a particular pathogen or confer long-lasting immunity.
In contrast, adaptive immunity develops in response to specific antigens. Antigen specificity allows for the generation of immune responses that are tailored to specific pathogens or pathogen-infected cells. This ability to respond is then retained after the pathogen has been eliminated, in the form of immunological memory, which allows the adaptive immune system to mount faster and stronger attacks each time the pathogen is encountered.
Cells and Receptors of the Adaptive Immune System
In the adaptive immune system, specialized leukocytes, called T lymphocytes and B lymphocytes, or T cells and B cells, recognize foreign antigens. B cells are involved in the humoral (antibody-driven) immune response. T cells are involved in the cell-mediated immune response. Both B cells and T cells have cell surface receptors that recognize specific antigens. The human body generates hundreds of millions of these T-cell receptors (TCRs) and B-cell receptors (BCRs).
TCR and BCR Composition
TCRs are heterodimers, typically consisting of either an alpha (A) and a beta (B) chain (shown in the figure) or a gamma (G) and a delta (D) chain in combination with signaling molecules known as the dimeric cluster of differentiation 3 (CD3). BCRs are composed of two heavy (IGH) and two light chains (IG kappa/lambda [IGK/L]). To generate a receptor repertoire with sufficient diversity to recognize the vast number of potential antigens, the extracellular TCRA/B and BCR heavy and light chains contain a highly varied complementary determining region 3 (CDR3).
TCR and BCR Recombination
The CDR3 region of the TCRB and IGH chain is created by splicing together specific copies of three gene segments called variable (V), diversity (D) and joining (J) segments.
At the junctions between V-D and D-J segments, a varying number of nucleotides are deleted and randomly inserted, creating a unique receptor. It is these unique insertions and deletions that are responsible for the vast diversity found in the adaptive immune repertoire.
Immunosequencing TCR and BCR Diversity
Immunosequencing uses multiplex PCR to amplify the CDR3 region of TCRs and BCRs to capture the receptor identity. The resulting nucleotide sequence may be used as an identifier or ‘tag’ for a particular T-cell or B-cell clone across different samples. Combined with the quantitative property of the assay, this provides a useful way to track clonal expansions and contractions of the adaptive immune repertoire over time in the same patient.
Immunosequencing can be used by researchers to:
- Deepen our understanding of basic immunology
- Facilitate research in immune-mediated diseases
- Identify new prognostic and diagnostic biomarkers
- Uncover mechanisms of action of therapeutic agents
- Track response to treatment