IMM: BLOCK 2: LECTURE 5: RECEPTORS

Somatically Generated Receptors of the Adaptive Immune System

• Receptors created in lymphocytes of an individual through random somatic chromosomal rearrangements and mutations
• Vast array of receptors specific for molecular details found in unique epitopes

Cell Surface Receptor Diversity

• Receptors of the innate immune system (PRRs and complement receptors) are limited in number and diversity
• Somatically generated receptors of lymphocytes in the adaptive immune system use random combinations of genes

Immunoglobulins (Ig) & T-cell receptors (TCRs)

• Antigen receptors of adaptive immunity

B -Cell Receptors

• Cell surface bound monomeric immunoglobulin associated with disulfide-linked heterodimers called Igα & Igβ
• BCR binds an epitope
• Specialized cytoplasmic tails of Igα & Igβ activate an intracellular signaling cascade that leads to B-cell activation
• Some activated B cells terminally differentiate into plasma cells that secrete immunoglobulins

T-Cell receptors (TCRs)

• Heterodimers, consisting of either an αβ or a γδ chain pair
• Always membrane bound and recognize antigen combined with MHC molecules
• Associated with CD3 complex
• CD3 complex links TCR to intracellular signaling molecules.
• An accessory molecule (CD4 OR CD8) serves as a coreceptor for TCR *

The T-cell Receptor Resembles a Membrane-bound Fab Fragment of Immunoglobulin

• Membrane-bound heterodimer composed of an α chain and a β chain
• Extracellular portion of each chain contains two immunoglobulin-like domains:
  • Constant (C) domain
  • Variable (V) domain
• The 3D structure formed by the 4 immunoglobulin-like domains of TCR resembles the antigen-binding Fab fragment of antibody

T-cell receptor diversity is generated by gene rearrangement.

• DNA recombination assembles a V-region sequence for each chain
• For α chain, rearrangement of a Vα gene segment and a Jα gene segment creates a functional exon encoding the V domain.
• For β chain, rearrangement of a Vβ , a Dβ, & a Jβ gene segment creates functional V-domain exon.
• The assembled genes are transcribed and spliced to produce mRNA encoding α & β chains.

Expression of the T-cell receptor on the T-cell surface requires association with additional proteins

• α & β chains bind antigen and form core TCR
• This core αβ heterodimer associates with CD3γ & CD3δ & CD3ε & the ζ chain
• Transmembrane domains of α & β chains contain positively charged amino acids (+) that form strong electrostatic interactions with negatively charged amino acids (–) in transmembrane regions of CD3γ, δ, & ε chains.

There are two classes of T-cell receptor

• αβ T-cell receptor and γδ T-cell receptor have similar structures but different functions

The Organization of the Human T-cell Receptor γ-chain and δ-chain loci

• TCR γ & δ loci (like α & β loci) contain sets of variable (V), diversity (D), joining (J), & constant (C) gene segments
• δ locus is located within α-chain locus on chromosome 14, between clusters of Vα & Jα gene segments
• There are at least 3 Vδ gene segments, 3 Dδ gene segments, 3 Jδ gene segments, & 1 Cδ gene segment
• Vδ segments are interspersed among Vα and other gene segments
• This arrangement means that DNA rearrangement within α-chain locus results in deletion of δ-chain locus.
• The γ locus (chromosome 7) resembles β locus, with 1 set of V segments & 2 C gene segments each with its own set of J segments.

Kristel Yee Mon, Ph.D.

• Studying a rare subset of T cells that may be a biomarker for patient outcome after infection with SARS-CoV2
• Studying chemically enhancing innate immune cell types to better prime anti-tumor T cell killer function as a prospective cancer immunotherapy agent.