Antigen Receptors #10 (Exam 2)

BCR & TCR give enormous flexibility to …

pathogen recognition

Organization of the BCR genes

multiple gene segments in germ-line DNA that encode parts of the B cell receptor (Ig) are rearranged & brought together to encode a functional B cell receptor (and antibody)

• light chain and heavy chain

V (D) J Recombination

the process where DNA is recombined during lymphocyte development to stitch together a unique TCR/BCR

• two light chains (light chain)

• two heavy & two light chains (heavy chain)

BCR Recombination in Detail

• for light chain: one V region & J region are joined

• for heavy chain: one V region, one J region, and one D region are joined

• RAG1/2 are molecular scissors that cut at RSS (enzyme making cuts to DNA)

• RSS: Recombination Signal Sequence

Consequences of BCR Rearrangement

• a random paring of V, J, and D are created

• these pairings are near the antigen binding face of the antibody

• complementary specificity region → determines what gets what

Combinational Diversity

random joining of V, D, and J gene segments to create variable domains of BCR/antibody molecules

• antigen binding specificity dictated by both V_H and V_L domains

Sources of Diversity of BCR

Combinatorial

• many ways to make light chains & heavy chains → for them to be matched

Junctional

• “messy” joining of V, D, & J gene segments (RAG1/2 makes many DNA regions → many different combinations)

• nucleotides may be deleted or added at joints

Rearrangement is temporally controlled

Pro B cells are in the process of rearranging their heavy chain

Pre B cells are attempting to transport their BCR to the cell surface to receive signals through it

• First the rearranged heavy chain is tested with the “surrogate light chain”

• If signaling through the Pre-BCR works, the cell will start to rearrange its light chain and test that

Two light chain genes (kappa & lambda) are both recombined in the same way

• multiple versions of each light chain gene segment (V, J and C) are encoded in the genome and one location (locus)

• one gene segment of each kind is joined to form a modified DNA sequence that encodes the light chain

Allelic Exclusion shuts down one copy of BCR

• the process of immunoglobulin gene arrangement is tightly controlled so that only one heavy chain & one light chain are finally expressed, known as allelic exclusion

• ensures each B cell produces only one immunoglobulin of a single antigen specificity

B cells can change their heavy chain constant region / class switch recombination

• Naive B cells always have IgD and IgM on their membrane

• When first activated, all B cells start by secreting IgM

• Activated B cells presenting antigen to T helper cells receive cytokine signals that induce them to class-switch to other isotopes (change which C_H domains they use)

3 Signals required for CSR

• Cytokines, CD40L/CD40, and TCR/MHC II Complex

Class Switch Recombination (CSR) in detail

• permanent, irreversible class switch recombination after cuts

• can use the cut parts to make different forms

• cytokines → initiate class switching

• uses “switch sequences” & a different molecular “scissors” than VDJ recombination

TCRs assembled very similarly to BCRs

• Receptor Structure:

  • BCRs:

    • Made up of two chains: one heavy chain and one light chain.

    • The variable regions of the heavy and light chains form the antigen-binding site, which can recognize a wide range of antigens (proteins, carbohydrates, lipids, etc.).

    • BCRs also have a membrane-bound form (the receptor itself) and a secreted form (antibodies produced by plasma cells).

  • TCRs:

    • Composed of two chains: one alpha chain and one beta chain (or gamma and delta chains in some cases).

    • The variable regions of the alpha and beta chains together form the antigen-binding site, but TCRs can only recognize peptide fragments presented by MHC molecules.

    • TCRs are always membrane-bound and are never secreted like antibodies.

• Antigen Type:

  • BCRs: Recognize a broad range of whole antigens in their natural, unprocessed form (e.g., proteins, carbohydrates, lipids, etc.). BCRs can bind directly to native antigens in 3D or linear structure.

  • TCRs: Recognize only peptide fragments, which are derived from processed proteins. These peptides must be presented on the surface of antigen-presenting cells (APCs) by MHC molecules (Major Histocompatibility Complex).

• Antigen Presentation:

  • BCRs: Directly bind to antigens in their native form, either floating in solution or displayed on the surface of a pathogen.

  • TCRs: Cannot bind native antigens. TCRs require that antigens be processed into small peptide fragments by APCs and presented on MHC Class I or MHC Class II molecules.

• Effector Functions:

  • BCRs: Once the BCR binds to an antigen, B cells can differentiate into plasma cells, which produce and secrete antibodies that neutralize pathogens, mark them for destruction, or block their entry into host cells.

  • TCRs: T cells do not secrete their receptors. Instead, once a TCR binds to an antigen-MHC complex, the T cell carries out its function:

    • Helper T cells (CD4+): Help activate B cells, cytotoxic T cells, and other immune responses.

    • Cytotoxic T cells (CD8+): Directly kill infected or abnormal cells.

TCR Rules

1) Membrane Bound only!

2) No Class switching

3) No somatic hypermutation

4) Allelic exclusion applies to TCR too