Immunology: Lymphocyte Development, Antigen Receptors, and MHC Biology

Comprehensive practice vocabulary flashcards covering B-cell development, antibody structure, isotypes, V(D)J recombination, T-cell receptors, MHC processing pathways, and thymic selection.

Passive Immunity (Ehrlich, von Behring, Kitasato)

The transfer of preformed protective antibodies or serum from an immunized individual or animal to a non-immunized recipient, providing immediate protection without endogenous activation.

Gamma Globulins ($\gamma$-globulins)

The electrophoretic serum protein fraction isolated by Arne Tiselius and Elvin Kabat that contains immunoprotective antibodies, also known as immunoglobulins.

Clonal Selection Theory Support (Nossal and Lederberg)

The immunological tenet established by proving that single isolated B cells produce antibodies reactive to only one Salmonella strain, thereby disproving the induced fit model.

Papain Digestion

Proteolytic cleavage of an antibody yielding three fragments at a $2:1$ ratio: two antigen-binding Fragment Antigen-Binding (Fab) arms and one crystallizable Fragment Crystallizable (Fc) stem.

$\beta$-Mercaptoethanol Reduction

Chemical reduction that cleaves interchain disulfide bonds in an antibody molecule, separating it into heavy (H) and light (L) polypeptide chains at a $1:1$ ratio.

Fragment Antigen-Binding (Fab)

The univalent antigen-binding portion of an antibody generated by papain cleavage, consisting of a complete light chain ($V_L$ and $C_L$) linked to the $V_H$ and $C_H1$ domains of a heavy chain.

Fragment Crystallizable (Fc)

The non-antigen-binding crystallizable portion of an antibody generated by papain cleavage, composed exclusively of heavy chain constant domains ($C_H2$ and $C_H3$) that interact with effector Fc receptors and complement.

B-Cell Receptor (BCR)

The membrane-bound form of an immunoglobulin anchored in the B-cell plasma membrane by a hydrophobic carboxyl-terminal transmembrane segment, associated with signaling subunits.

$Ig\alpha/Ig\beta$ ($CD79\alpha/\beta$) Heterodimer

A disulfide-linked transmembrane heterodimer noncovalently associated with the BCR, containing long cytoplasmic tails with immunoreceptor tyrosine-based activation motifs (ITAMs) essential for signal transduction.

Immunoreceptor Tyrosine-Based Activation Motif (ITAM)

A conserved amino acid sequence containing two tyrosine residues located approximately $10$ residues apart that undergo phosphorylation upon antigen receptor cross-linking to initiate intracellular signaling cascades.

B-Cell Coreceptor Complex

A membrane protein triad consisting of CD21 (CR2), CD19, and CD81 (TAPA-1); CD21 binds C3d-opsonized antigens to enhance avidity, while CD19 and CD81 transduce activating signals.

Complementarity-Determining Regions (CDRs)

Three hypervariable polypeptide loops (CDR1, CDR2, CDR3) clustered at the N-terminal variable domains ($V_H$ and $V_L$) of immunoglobulins and TCRs that make direct physical contact with antigen; CDR3 displays the highest variability.

Immunoglobulin (Ig) Fold Domain

A conserved protein domain of approximately $110$ amino acids structured into two antiparallel $\beta$-pleated sheets linked by an intrachain disulfide bond, forming a stable hydrophobic sandwich.

Immunoglobulin M (IgM)

The first antibody class produced during a primary immune response; secreted as a planar pentamer stabilized by a J chain, providing $10$ antigen-binding sites with high avidity and superior classical complement activation.

Immunoglobulin G (IgG)

The predominant immunoglobulin class in serum ($70\text{--}75\%$), composed of four subclasses that mediate pathogen opsonization via $Fc\gamma$ receptors, antibody-dependent cellular cytotoxicity (ADCC), and placental transfer.

Immunoglobulin A (IgA)

The predominant antibody class in mucosal secretions (gut, tears, saliva, milk), secreted primarily as a dimer held together by a J chain and protected from enzymatic degradation by a secretory component.

Polymeric Immunoglobulin Receptor (pIgR)

A receptor expressed on the basolateral surface of epithelial cells that binds J-chain-containing dimeric IgA (or pentameric IgM) to mediate transcytosis into mucosal secretions, cleaving to yield the secretory component.

Immunoglobulin E (IgE)

A low-abundance serum antibody that binds with high affinity to $Fc\epsilon RI$ receptors on mast cells, basophils, and eosinophils, triggering degranulation and histamine release in antiparasitic defense and allergic reactions.

Immunoglobulin D (IgD)

A minor serum immunoglobulin ($< 1\%$) co-expressed with IgM on mature naive B cells; also present in upper respiratory secretions where it binds basophils and mast cells to trigger antimicrobial peptide and cytokine release.

Zone of Equivalence

The optimal ratio of multivalent antibody to polyvalent antigen in solution that allows maximal cross-linking and lattice formation, resulting in visible immunoprecipitation.

Hemagglutination Assay

An agglutination technique using serial dilutions of antibody against red blood cells; cross-linking forms an expanded settling lattice (positive reaction), whereas lack of agglutination results in a compact cellular button.

Hybridoma Technology (Köhler and Milstein)

The fusion of antibody-producing spleen plasma cells with immortal HGPRT-deficient myeloma cells using polyethylene glycol (PEG), followed by selection in HAT medium to generate monoclonal antibodies of single specificity.

Somatic DNA Recombination (Tonegawa)

The genomic rearrangement mechanism demonstrated by Susumu Tonegawa showing that immunoglobulin V and C gene segments are separated in germline DNA but brought adjacent to each other in differentiated B cells.

Recombination Signal Sequence (RSS)

Conserved DNA motifs flanking V, D, and J segments consisting of a conserved $7\text{ bp}$ heptamer ($5'\text{-CACAGTG-}3'$), a non-conserved $12\text{ bp}$ or $23\text{ bp}$ spacer, and a conserved $9\text{ bp}$ nonamer ($5'\text{-ACAAAAACC-}3'$).

12/23 Rule

The invariant rule governing V(D)J recombination stating that gene segment joining occurs only between an RSS containing a $12\text{ bp}$ spacer and an RSS containing a $23\text{ bp}$ spacer.

RAG1/2 Recombinase Complex

A lymphoid-specific enzyme complex that binds RSSs; RAG1 mediates DNA cleavage by nicking and forming covalently sealed hairpins at coding ends, while RAG2 directs epigenetic targeting. Deficiency causes SCID.

Artemis Endonuclease

A DNA repair enzyme that, upon phosphorylation by the DNA-PKcs kinase complex, cleaves the hairpin-sealed coding ends generated by RAG, introducing single-stranded overhangs that yield palindromic P-nucleotides.

Terminal Deoxynucleotidyl Transferase (TdT)

A lymphoid-specific enzyme that randomly adds nontemplated (N) nucleotides in a template-independent manner to the free $3'$ ends of cleaved DNA during coding joint assembly.

P-Nucleotide Addition

The generation of short palindromic nucleotide sequences at coding joints created when Artemis cuts the hairpin loop asymmetrically and DNA repair enzymes fill in the resulting single-stranded overhang.

Signal Joint vs. Coding Joint

The signal joint is the precise, direct ligation of blunt-ended heptamer RSS ends (often circularized as a DNA excision circle); the coding joint is the imprecise, variable joining of V, D, and J coding sequences.

Surrogate Light Chain (SLC)

An invariant polypeptide pair consisting of VpreB and $\lambda5$ that pairs with the rearranged $\mu$ heavy chain in pro-B cells to assemble the pre-B-cell receptor (pre-BCR).

First B-Cell Checkpoint

A developmental testing event in large pre-B cells where successful pre-BCR signaling verifies functional $\mu$ heavy-chain rearrangement, halting heavy-chain rearrangement (allelic exclusion) and driving proliferation.

Receptor Editing

A central tolerance mechanism in immature B cells wherein an autoreactive receptor triggers reactivation of RAG1/2 genes to rearrange alternative light-chain gene segments, altering antigen specificity.

Subtractive Hybridization (Hedrick and Davis)

A molecular technique used to discover TCR genes by hybridizing membrane-bound T-cell cDNA with B-cell mRNA, discarding shared hybrids, and isolating clones unique to the T-cell lineage.

T-Cell Receptor (TCR)

A clonotypic heterodimer composed of either $\alpha\beta$ or $\gamma\delta$ chains containing variable and constant Ig-like domains, anchored by a transmembrane segment with positively charged residues.

CD3 Signaling Complex

An invariant complex of three dimers ($\delta\epsilon$, $\gamma\epsilon$, and $\zeta\zeta$ or $\zeta\eta$) noncovalently associated with the TCR that transduces antigen recognition signals via cytoplasmic ITAMs ($\zeta$ chains contain 3 each).

CD4 Coreceptor

A monomeric membrane glycoprotein with four extracellular Ig-like domains ($D_1\text{--}D_4$); the $D_1$ domain binds conserved $\alpha2/\beta2$ clefts of MHC class II molecules to stabilize the TCR interaction and recruit Lck.

CD8 Coreceptor

A disulfide-linked $\alpha\beta$ heterodimer with extended stalks that binds to the conserved $\alpha2/\alpha3$ domains of MHC class I molecules, facilitating cytotoxic T-cell activation.

Major Histocompatibility Complex (MHC) Class I

A cell-surface heterodimer composed of a polymorphic $\alpha$ chain ($\alpha1, \alpha2, \alpha3$) and non-covalently associated invariant $\beta_2$-microglobulin; its closed groove binds endogenous peptides of $8\text{--}10$ amino acids.

Major Histocompatibility Complex (MHC) Class II

A cell-surface heterodimer composed of non-covalently linked polymorphic $\alpha$ ($\alpha1, \alpha2$) and $\beta$ ($\beta1, \beta2$) chains; its open-ended groove binds exogenous peptides of $13$ or more amino acids.

$\beta_2$-Microglobulin ($\beta_2\text{m}$)

An invariant, non-MHC-encoded light chain of the MHC class I heterodimer that lacks a transmembrane domain and is strictly required for stable class I surface folding and expression.

MHC Restriction (Zinkernagel and Doherty)

The immunological principle demonstrating that T-cell receptors recognize foreign antigen only when presented in complex with self-MHC molecules encoded by the individual's own MHC haplotype.

Anchor Residues

Conserved amino acid positions within a peptide that fit into specific chemical pockets in an MHC binding groove, anchoring the peptide and conferring promiscuous binding capabilities.

Immunoproteasome

A specialized cytokine-induced form of the proteasome (containing $\beta1i$, $\beta2i$, and $\beta5i$ catalytic subunits) that preferentially cleaves intracellular proteins into peptide fragments optimal for MHC class I loading.

Transporter Associated with Antigen Processing (TAP1/2)

An ATP-dependent heterodimeric transporter in the RER membrane that translocates cytosolic proteasome-generated peptides into the lumen of the RER for loading onto MHC class I molecules.

Tapasin

An ER molecular chaperone bridging the newly formed MHC class I–$\beta_2\text{m}$–calreticulin–ERp57 complex to TAP, facilitating high-affinity peptide capture before exit to the Golgi.

Invariant Chain (Ii / CD74)

A non-polymorphic chaperone that trimerizes in the RER to block endogenous peptides from binding the MHC class II groove and directs the complex via sorting signals to the endocytic pathway.

Class II-Associated Invariant Chain Peptide (CLIP)

The residual polypeptide fragment left sitting in the MHC class II antigen-binding cleft after lysosomal proteases (cathepsins) digest the invariant chain within acidic endosomal vesicles.

HLA-DM

A nonclassical, non-cell-surface MHC class II-like protein in the MIIC compartment that catalyzes the removal of CLIP and the loading of high-affinity antigenic peptides onto classical MHC class II.

Cross-Presentation (Cross-Priming)

The pathway in professional antigen-presenting cells (predominantly dendritic cells) whereby exogenous antigens are retro-translocated into the cytosol, processed, and presented on MHC class I molecules to activate naive CD8+ T cells.

Macroautophagy

An unconventional processing pathway in which cytosolic materials are sequestered in double-membrane autophagosomes that fuse with lysosomes, allowing degradation and loading of endogenous peptides onto MHC class II.

Chaperone-Mediated Autophagy (CMA)

An alternative pathway where cytosolic proteins bound by Hsc70 chaperones translocate through multimerized LAMP-2A membrane pores directly into the lysosome for degradation and presentation on MHC class II.

Notch Signaling

The essential receptor-ligand interaction in the thymic microenvironment that commits common lymphoid progenitors (CLPs) to the T-cell lineage rather than the default B-cell lineage.

Double-Negative (DN) Stages

The earliest phase of thymocyte development characterized by the absence of CD4 and CD8, subdivided into DN1 ($\text{c-Kit}^{++}\text{CD44}^+\text{CD25}^-$), DN2 ($\text{c-Kit}^{++}\text{CD44}^+\text{CD25}^+$), DN3 ($\text{c-Kit}^+\text{CD44}^-\text{CD25}^+$), and DN4 ($\text{c-Kit}^{\text{low}/-}\text{CD44}^-\text{CD25}^-$).

$\beta$-Selection

A critical checkpoint at the DN3 stage where a successfully rearranged TCR $\beta$ chain pairs with invariant pre-T$\alpha$ ($\text{pT}\alpha$) to form the pre-TCR, arresting further $\beta$ rearrangement, inducing allelic exclusion, and driving proliferation.

Double-Positive (DP) Thymocyte

A developmental stage ($CD4^+CD8^+$) comprising over $80\%$ of thymocytes in the cortex that expresses mature $\alpha\beta$ TCRs and undergoes positive and negative selection.

Positive Selection (Thymus)

The survival and differentiation of cortical DP thymocytes whose TCRs engage self-peptide–self-MHC complexes presented by cortical thymic epithelial cells (cTECs) with low-to-intermediate affinity, establishing MHC restriction.

Death by Neglect

The apoptotic fate undergone by $90\text{--}96\%$ of DP thymocytes whose TCRs have insufficient or no affinity for self-peptide–self-MHC complexes presented on cTECs in the thymic cortex.

Kinetic Signaling Model

The accepted lineage commitment model proposing that all DP thymocytes initially downregulate CD8 to become $CD4^+CD8^{\text{lo}}$; continuous TCR signaling drives commitment to CD4+ helper T cells, whereas interrupted signaling with IL-7 rescue drives differentiation into CD8+ cytotoxic T cells.

Negative Selection (Central Tolerance)

The induction of apoptosis (clonal deletion) in thymocytes expressing TCRs with dangerously high affinity for self-antigen–MHC complexes in the thymic medulla, eliminating autoreactive T cells.

Autoimmune Regulator (AIRE)

A transcriptional factor expressed in medullary thymic epithelial cells (mTECs) that recruits histone acetyltransferases (CBP) to open chromatin, directing ectopic expression of tissue-specific antigens for negative selection.

Autoimmune Polyglandular Syndrome Type 1 (APS-1 / APECED)

A severe multi-organ autoimmune disorder caused by loss-of-function mutations in the AIRE gene, clinically characterized by hypoparathyroidism, primary adrenocortical failure, and chronic mucocutaneous candidiasis.

Regulatory T Cells (Tregs)

A lineage of immunosuppressive $CD4^+CD25^+$ T cells defined by expression of the master transcription factor FoxP3 that suppress autoreactive responses via cytokine deprivation (IL-2 absorption), inhibitory cytokines (TGF-$\beta$, IL-10), APC inhibition, and cytotoxicity.

Superantigens

Microbial proteins that cross-link the outer side of the TCR $V\beta$ domain with the invariant $\alpha$ chain of MHC class II molecules outside the peptide-binding cleft, nonspecifically activating up to $5\%$ of all peripheral T cells and triggering massive cytokine release.

Three-Signal Hypothesis of T-Cell Activation

The model defining naive T-cell activation: Signal 1 is TCR ligation by peptide-MHC; Signal 2 is costimulation between CD28 on the T cell and CD80/CD86 on the APC; Signal 3 consists of polarising cytokines (e.g., IL-2, IL-12, TGF-$\beta$) directing differentiation and proliferation.