Immunology (Lippincott Illustrated Reviews Series) 2nd Edition

Chapter 10: Lymphocyte Activation


Compared with innate immune responses, adaptive immune responses against newly encountered antigens initially develop slowly. Although many self-reactive cells are eliminated during development, lymphocytes undergo a further set of time-consuming checks and balances to minimize the potential for adverse immune responses. This system of checks and balances is imposed by different cell types for recognition, regulation, and effect or function. T cells play a central role as arbiters of adaptive immune function, and because of this role, the manner in which T cells recognize and are activated by epitopes is stringently regulated. It is useful to think of the innate immune system as the gatekeeper for adaptive immune responses (Fig.10.1). Adaptive immune system effect or responses often activate and focus cells and/or molecules of the innate system on targets selected by the lymphocytes.


Phagocytes sample their environment by phagocytosis and macropinocytosis. Ingested proteins are enzymatically degraded, and some of the resulting peptide fragments are loaded into MHC class II (forming pMHC class II) molecules in a process called antigen presentation. Some pathogens avoid phagocytotic and macropinocytotic mechanisms altogether or infect cells that do not express MHC class II molecules. Such antigens are broken down, and their peptide fragments are loaded into MHC class I (forming pMHC class I) molecules (Fig.10.2).

A. Presentation by MHC class II

Dendritic cells located at potential microbial portals of entry (e.g., skin and mucous membranes) and in other tissues and organs serve as sentinels (see Fig. 4.5). Immature dendritic cells are voracious eaters that ingest large amounts of soluble and particulate matter by phagocytosis and macropinocytosis. Phagocytosis involves the engagement of cell surface receptors (e.g., Fc receptors, heat shock proteins, and low-density lipoprotein-binding scavenger receptors) associated with specialized regions of the plasma membrane called clathrin-coated pits (Fig.10.3). Receptor engagement induces actin-dependent phagocytosis and receptor internalization to form small phagosomes or endocytic vesicles. Immature dendritic cells also sample large amounts of soluble molecules as well as particles present in the extra cellular fluids bymacropinocytosis, a process in which cytoplasmic projections (cytoplasmic ruffles) encircle and enclose extracellular fluids to form endocytotic vesicles (Fig.10.4). Macropinocytosis does not require clathrin-associated receptor engagement. Lysosomes (enzyme-containing cytoplasmic vesicles) fuse with the endocytic vesicles derived from phagocytosis or macropinocytosis (see Fig. 10.2). Within this newly formed phagolysosome, ingested material is enzymatically degraded.


Figure 10.1

Interactions of the innate and adaptive immune systems.


Figure 10.2

Antigen presentation pathways. Extracellular antigens (e.g., bacteria, cells, and many soluble molecules) enter the cell by phagocytosis or macropinocytosis packaged in phagocytic vesicles. Inset: Phagocytic vesicles fuse with enzyme-(lysozymes) containing vesicles (lysosomes) to form phagolysosomes that enzymatically degrade the ingested material. The lysosomal enzymes proteolytically degrade the ingested material into peptides in the late phagosome. The late phagosome will fuse with vesicles containing MHC class II. Intracellular pathogens (e.g., viruses and certain bacteria) and some antigens directly enter the cell’s cytoplasm, circumventing the phagocytic apparatus. Intracellular antigens are degraded by the proteasome into peptides that are loaded into MHC class I (pMHC class I) for display on the cell surface.

When an immature dendritic cell senses an invasive threat, it rapidly begins to mature. Threats are detected by the same cell surface receptors used by the innate immune system. Direct sensing occurs through engagement of pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) on viruses, bacteria, fungi, and protozoa. Engagement of other receptors (e.g., those that detect antibodies or complement molecules that have bound to microbes) is responsible for the indirect sensing of perceived threats.

Although the mechanisms responsible for dendritic cell maturation remain to be clarified, we know that threat sensing causes the dendritic cells to migrate to nearby lymph nodes, decrease their phagocytic and macropinocytic activity, and increase their MHC class II synthetic activity. MHC class II α and β polypeptides, together with an invariant chain, are assembled as a complex within the endoplasmic reticulum (Fig. 10.5). Vesicles bud off from the endoplasmic reticulum to fuse with the peptide-containing, acidic phagolysosomes. The invariant chain disintegrates in the acidic environment of the newly formed vesicle, allowing phagolysosome-derived peptides to occupy the peptide-binding groove of the MHC class II molecule. The pMHC class II complex is transported to the cell surface for display and possible recognition by CD4+ T cells. MHC class II molecules make no distinction between peptides of self and nonself origin. Self antigens displayed on the phagocyte surface usually go unrecognized because most self-reactive CD4+ T cells have been eliminated during development.

B. Presentation by MHC class I

Not all antigens enter cells by phagocytosis or macropinocytosis. Some pathogens avoid phagocytes and endocytic vesicles entirely. Intracellular microbes and viruses bind to cell membranes and directly enter the cytoplasm of the host cell (Fig. 10.6). These pathogens are processed differently.

Nucleated cells normally degrade and recycle cytoplasmic proteins. Both self and nonself cytoplasmic proteins targeted for destruction are covalently tagged with ubiquitin, a highly conserved 76-amino-acid protein. The selection mechanisms for protein ubiquination are not known. Binding of one or more ubiquitin molecules to a protein selects it for destruction by the proteasome, a large proteolytic enzyme complex within the cytoplasm. Proteasome-generated peptides of 6 to 24 amino acids are transported to the endoplasmic reticulum by the transporter associated with antigen processing (TAP-1 and TAP-2). The TAP heterodimer allows peptides to load into MHC class I (pMHC class I). These then move to the Golgi. Special transport exocytic vesicles containing pMHC class I bud from the Golgi and are rapidly transported to the cell surface for display and recognition by the appropriate CD8+ T cells. MHC class I molecules make no distinction between peptides of self and nonself origin. However, self peptides displayed on the phagocyte surface usually go unrecognized because CD8+ T cells that are potentially reactive to self peptides are removed during thymic selection.


Figure 10.3

Phagocytosis. Cells, particles, and molecules are captured by PRRs associated with clathrin-coated pits. Clathrin-associated membrane invaginates and pinches off to form a phagosome. Clathrin is recycled back to the cell membrane to help form new coated pits.


Figure 10.4

Macropinocytosis. 1. Cytoplasmic protrusions or ruffles engulf and surround microbes, particles, or molecules to form a cytoplasmic vesicle (2) that fuses with a lysosome (3) to form a phagolysosome. 4. Vesicles containing enzymatically degraded material fuse with vesicles containing MHC class II (see Fig. 10.6). 5. Empty phagolysosomes are recycled back to the cell membrane.


Figure 10.5

Presentation of extracellular antigens. Antigens of extracellular origin (left side of diagram) or of self origin (right side) are degraded within phagolysosomes. MHC class II αβ heterodimers together within variant chain are assembled within the endoplasmic reticulum. Vesicles containing MHC class II 1 invariant chain bud off from the endoplasmic reticulum to fuse with peptide-rich vesicles that bud off from the phagolysosome. The acidic environment of the fused vesicle causes the invariant chain to disintegrate, allowing peptides to occupy the peptide-binding groove of the MHC class II molecule. Invariant chain-lacking MHC class II molecules that do not bind a peptide disintegrate in the acidic environment of the vesicle. The exocytotic vesicle containing pMHC class II fuses with the cell’s plasma membrane, and the pMHC class II molecules are displayed on the cell surface for recognition by TCRs of CD4+ T cells.


Figure 10.6

Presentation of intracellular or cytoplasmic antigens. Cytoplasmic proteins of both self and nonself origin may be marked for destruction by the covalent attachment of ubiquitin, which targets them for proteolytic degradation by the proteasome enzyme complex. Proteasome-generated peptide fragments within the cytoplasm are transported into the endoplasmic reticulum by gatekeeper TAP-1 and TAP-2 heterodimers. Calnexin, a chaperone molecule, binds to newly synthesized MHC class I molecules to allow β2 microglobulin to form a MHC class I:β2 complex. Calnexin is replaced by another chaperone molecule, calreticulin. A third chaperone molecule, tapasin, associated with the TAP heterodimer, assists possible loading into the peptide into the MHC class I:β2 complex. The MHC class I:β2complex rapidly disintegrates if a suitable peptide is not loaded. Exocytotic vesicles containing the newly formed pMHC class I complexes bud off from the endoplasmic reticulum and are transported for display on the cell surface by CD8+ T cells with the appropriate TCR.

MHC restriction

A useful memory device to remember CD4/CD8 MHC restriction is the “Rule of eight:”

CD4 × pMHC class II 5 8

CD8 × pMHC class I 5 8

T cells of the γδ lineage often express neither CD4 nor CD8, and their restriction is unclear.

Intracellular pathogens

I just read that the TCRs of CD4+ T cells recognize pMHC class II complexes of exogenous origin. How can a peptide derived from an intracellular pathogen that circumvents phagolysosome vesicles load into a class II molecule?

To avoid detection by the adaptive immune system, some pathogens employ a “stealth mechanism” by circumventing phagolysosome vesicles altogether. Others may enter the cell in phagosomes but are able to leave them and enter the cytoplasm. But their ruse is not perfect, as some infected cells die, prompting dendritic cells to take up dead cells and cellular debris by either phagocytosis or macropinocytosis. The proteolytic peptides are then displayed in class II molecules. Mystery solved.


T cells largely direct the adaptive immune response. Unlike innate immune system receptors and BCRs, TCRs cannot recognize soluble molecules. T cells recognize only peptides presented by MHC class I or class II molecules that are displayed by antigen-presenting cells (APC). The nature of the adaptive immune response is strongly influenced by how epitopes are presented by APCs. The interface between APC and a previously unactivated (naïve) T cell is called the immunologic synapse.

A. Immunologic synapse

The immunologic synapse is initiated by TCR recognition of pMHC (Fig. 10.7). The weak interaction of TCR with pMHC is stabilized by the interaction with CD4 or CD8 molecules that bind to the “constant” nonpeptide-binding portions of pMHC class II and class I, respectively. Formation of the pMHC:TCR:CD (4 or 8) complex provides a first signal though the TCR-associated CD3 complex to the T cell. This first signal is necessary but not sufficient to stimulate a naïve T cell to proliferate and differentiate. A second signal (or more properly, a group of signals) provided by one or more costimulatory molecules is also required for T cell activation. The first and second signals initiate intracellular signaling cascades activating one or more transcription factors leading to specific gene transcription. Without costimulation, T cells either become selectively unresponsive, a condition known as anergy or undergo apoptosis.


Figure 10.7

Immunologic synapse. Extracellular antigens are displayed (presented) by MHC class II molecules by APC. TCRs of circulating CD4+ T cells that recognize peptide and MHC class II (pMHC class II) form a weak bond that is stabilized by the noncovalent interaction of the T cell’s CD4 molecule with the nonpeptide-binding portion of MHC class II. Inset. Adhesion molecules expressed by T cells (leukocyte function antigen-, LFA-1, or CD11a/CD18) interact with ICAM-1 (immune cell adhesion molecule-1 or CD54) on APC. LFA-1:ICAM-1 complexes move away from the pMHC:TCR:CD4 complex. At the same time, CD2:LFA-3 (CD2:CD58) and costimulatory complexes (e.g., CD28:CD80/86) move toward the pMHC:TCR:CD4 complex.

B. T cell signal transduction

The immunologic synapse stabilizes T cell-APC interaction and promotes the migration of adhesion molecules within the T cell membrane. Cytoplasmic tails of some of these molecules contain immunoreceptor tyrosine–based activation motifs (ITAMs) that initiate a signaling cascade when brought into close proximity (Fig.10.8). The cytoplasmic tails of CD3 complex molecules (CD3ε, γ, δ, and CD247 ζ) bear ITAMs. In contrast, the cytoplasmic tails of the TCR lack ITAMs. The first signal for T cell activation is provided by the signals transduced following TCR engagement of a peptide presented by pMHC II and tyrosine phosphorylation of ITAMs on the cytoplasmic tails of CD3 complex molecules (Fig.10.9). Costimulatory molecules provide the second signal for T cell activation (Fig. 10.10).


Figure 10.8

Immunoreceptor activation motifs (ITAMs). Ligand engagement leads to polypeptide dimerization, activation of tyrosine kinases, and the phosphorylation of tyrosine residues within specialized intracellular portions of receptor or accessory polypeptides. These ITAMs contain four amino acids (indicated as two Xs flanked by tyrosine (Tyr) and lysine (Lys). Multiple ITAMs are located at 10- to 12-amino acid intervals along the cytoplasmic tail.

C. CD4+ T cell maturation

The initial encounter of T cells with antigen is called priming, and the nature of this encounter is crucial to the development of the subsequent adaptive immune response. Primed CD4+ T cells are termed T helper or Th cells because they are instrumental in “helping” other leukocytes respond (Fig. 10.11). Upon activation, naïve CD4+ Th precursor (Thp) cells are stimulated to secrete various cytokines and express cell-surface cytokine receptors, becoming pathway-uncommitted Th0 cells (Fig. 10.11). CD4+ Th0 cells may mature along one of two functional pathways. The developmental pathway that the Th0 follows depends on the nature of signals it receives at the time it interacts with the APC. In the presence of microbe-derived lipopolysaccharide, APCs secrete IL-12 and other cytokines that increase leukocyte recruitment and activation. CD4+ T cells generally respond to these signals by recruiting and activating phagocytic cells or by activating cytotoxic T lymphocytes (CTL). These T cells are known as Th1 cells. T cells that develop along the other pathway are known as Th2 cells and generally respond to extracellular pathogens by stimulating B cells to differentiate into antibody-secreting plasma cells. In other cases, the presence of IL-4 may lead Th0 to follow the Th2 differentiation pathway. Among the functional roles of Th2 cells is the production of cytokines responsible for the proliferation and activation of B cells and their differentiation into plasma cells or memory B cells.


Figure 10.9

Details of T cell “first signal” transduction. 1. The T-cell receptor (TCR) engages a peptide presented by MHC class II (pMHC II). 2. CD4 stabilizes this complex by binding noncovalently to the nonpeptide-binding region of MHC class II, causing (3) the LCK tyrosine kinase to phosphorylate immunoreceptor activation motifs (ITAMs) on the cytoplasmic tails of CD3 complex molecules (CD3 ε, γ, and δ and the CD247 ζ-ξ homodimer). 4. ZAP-70 tyrosine kinase “docks” on the phosphorylated ITAMs and phosphorylates the remaining CD247 ζ-ζ ITAMs and phosphorylates and activates phospholipase C-γ (PLC-γ). 5. PLC-γ cleaves phosphatidyl inositol 4,5-bi(s) phosphate (PIP2) into diacylglycerol (DAG) and inositoltri(s) phosphate (IP3). 6. IP3 promotes release of calcium from intracellular stores, and calcium together with DAG activates protein kinase C (PKC) and the protein phosphatase, calcineurin. 7. PKC phosphorylates IκB (inhibitor of nuclear factor kappa B, NFκB) causing the inhibitor to dissociate from NFκB. Likewise, calcineur in dephosphorylates and activates nuclear factor of activated T cells (NFAT). Both transcription factors (NFκB and NFAT) migrate to the nucleus, where they activate genes. 8. ZAP-70 also phosphorylates the linker of activation for T cells (LAT), which activates the guanine nucleotide exchange factors (GEFs), ras and rac. 9. Ras and rac initiate phosphorylation cascades (see Figs. 6.10 and 6.11) to activate the AP-1 family of transcription factors.


Figure 10.10

The second signal: Costimulation. A second signal (costimulation) is required for T cell activation. Upon formation of the immunologic synapse (see Fig. 10.9), the common leukocyte antigen (CD45) dephosphorylates and activates Fyn kinase. Both CD28 (costimulatory molecule) and Fyn associate with inositol tri(s)phosphate kinase (IP3K) to activate Ras and initiate a phosphorylation/activation cascade (see Figs. 6.10 and 6.11).


Figure 10.11

Differentiation of CD4+ T helper 1 (Th1) and T helper 2 (Th2) lymphocytes.

D. CD8+ T cell maturation

Recognition of pMHC class I (first signal) displayed on the surface of an infected APC or other cell by naïve CD8+ T cell(s) causes them to express IL-2 receptors (IL-2R) (Fig. 10.12). Phagocytosis of the cellular debris of a virus-infected cell and display of viral pMHC class II by APC stimulates a CD4+ T cell to produce IL-2 and provides a second signal to the CD8+ T cell through its IL-2R. APC-CD4+ T cell interaction increases CD80/86 expression by APC. Interaction of APC CD80/86 with CD28 on CD8+ T cells promotes CD8+ T cell differentiation. Appropriately stimulated CD8+ T cells proliferate and differentiate into cytolytic effect or cells called cytotoxic T lymphocytes (CTL). Fully differentiated CTLs have granules that contain perforin, acytolytic protein, and granzyme, a protease, that function to induce apoptosis of the target cell expressing the appropriate pMHC class I complex (see Chapter 11).

E. Memory T cells

TCR engagement with the appropriate pMHC class II (first signal) and CD28 engagement with CD80/86 (second signal) stimulate CD4+ T cells to produce IL-2, express IL-2 receptors (IL-2R), and proliferate. In most stimulated CD4+ T cells, CD 152 (cytotoxic T lymphocyte-associated antigen-4 or CTLA-4), normally sequestered within the Golgi apparatus, travels to the cell membrane. There, it binds to CD80/86 with an avidity that is 100-fold greater than that of CD28 (Fig. 10.13). CD152 engagement inhibits T cell IL-2 mRNA expression and halts cell proliferation, thus ensuring that CD4+ T cell-mediated responses are self-limiting. However, if all CD4+ T cells were unable to respond on second exposure, the body would be at severe risk to subsequent encounters with the same infectious organism. Fortunately, some CD4+ T cells enter into a memory state. Memory T cells typically express CD28, increase their expression of some adhesion molecules but decrease their surface expression of CD62L (L-selectin). By increasing their expression of CD28, memory T cells are more likely to respond rapidly to CD80/86 displayed by APC. By decreasing L-selectin expression (CD62L), memory T cells no longer home to lymph nodes but home to sites of inflammation because of increased expression of other adhesion molecules. For some CD4+ T cells, the memory phenotype results in a change in their surface expression of CD45 from the naïve CD45RA to the memory CD45RO isoform.


Figure 10.12

CD8+ T cell activation.


Figure 10.13

Generation of memory T cells.


Figure 10.14

B-cell receptor (BCR). Surface-bound immunoglobulin functions as the epitope-specific BCR. All BCRs expressed by a single B cell have identical epitope specificity. Epitope binding causes conformational change in the BCR that transduces a signal to the cytoplasm via Igα and Igβ accessory molecules.


In contrast to TCRs, BCRs recognize and bind epitopes on either cell-bound or soluble molecules. The BCR complex of mature B cells contains membrane-bound immunoglobulin monomers associated with Igα and Igβ molecules (Fig. 10.14). Similar to the CD3 complex, the cytoplasmic tails of Igα and Igβ molecules contain ITAM motifs. BCR cross-linking initiates intracellular signaling. Because all of the immunoglobulins on a given B cell have the same specificity, an antigen must contain multiple identical epitopes for cross-linking to occur (Fig. 10.15). Cross-linking of BCRs induces tyrosine kinases such as lyn, lck, fyn, and blk to phosphorylate the Igα and Igβ ITAMs. ITAM phosphorylation allows docking of Syk and activation of phospholipase C-γ (PLC-γ to initiate a signal transduction cascade resulting in the activation of transcription factors (e.g., NFκB and NFAT) and gene activation. BCR binding initiates endocytosis, enzymatic degradation, and subsequent display of peptide fragments as pMHC class II complexes and cause the B cell to express costimulatory molecules. This allows the B cell to function as an APC for TCR recognition by a CD4+ T cell.

A. T-Independent activation

Some antigens are classified as T-independent (TI) to indicate that they activate B cells without help from T cells. TI antigens fall into two distinct groups (TI-1 and TI-2) based on how they activate B cells. TI-1 antigens are polyclonal activators that bind to surface structures other than BCRs. Therefore, they activate B cells irrespective of BCR epitope specificity. They are typically microbial in origin such as lipopolysaccharide. In high concentration, TI-1 antigens stimulate B cells to activate, proliferate, and increase immunoglobulin production and secretion, and for this reason, they are often called B cell mitogens. In low concentrations, TI-1 antigens stimulate antigen-specific T cells. TI-2 antigens contain repetitive epitopes and are often multivalent polysaccharides. In contrast to TI-1 antigens that stimulate both mature and immature B cells, TI-2 antigens specifically activate only mature B cells. Repetitive epitopes on polysaccharides bind to and cross-link specific BCRs (Fig. 10.15). The close proximity of Igα and Igβ cytoplasmic tail results in phosphorylation and initiation of a signal transduction cascade. It is not clear whether immune responses to TI-2 antigens are totally T-independent. Addition of even small numbers of T cells increases antibody production to TI-2 antigens.


Wiskott–Aldrich syndrome

The capsular polysaccharide of Haemophilus influenzae B is a TI-2 antigen. Antibody responses to H. influenzae are essential for protective immunity. Individuals with Wiskott–Aldrich syndrome, an immunodeficiency disease, respond poorly to protein antigens and not at all to polysaccharide antigens. Consequently, people with Wiskott–Aldrich syndrome are susceptible to infections by bacteria such as H. influenza that have polysaccharide capsules.


Figure 10.15

Details of the B cell signaling cascade. Cross-linking leads to BCR aggregation, and the close proximity of the cytoplasmic tails of the Igα and Igβ allows phosphorylation of their ITAMs by tyrosine kinases (lyn, blk, lyn, and lck). Syk docks, phosphorylates, and activates phospholipase C-γ (PLC-γ) and leads to the signal transduction cascade (see Figs. 6.10 and 6.11).

Sometimes, a second T-independent signal is provided to the B cell coreceptor complex in conjunction with complement components (Fig. 10.16). C3d or C3b binds to an antigen (e.g., a microbe) that is also bound to the BCR through epitope recognition. CD21 (type 2 complement receptor or CR2) binds to antigen-bound C3d or CD35 (type 1 complement receptor or CDR1) binds to antigen-bound C3b. Cell-membrane-bound CD19 and CD18 (or TATA-1) rapidly associate to form the B cell coreceptor complex (CD21:CD19:CD81). Once the B cell coreceptor complex is established, several tyrosine kinases (lyn or fyn and Vav or PI-3K) phosphorylate the cytoplasmic tail of CD19. At the same time, fyn, lyn, and/or blk phosphorylate ITAMs on Igα and Igβ to allow docking of Syk tyrosine kinase and the initiation of a signal transduction cascade.


Figure 10.16

B cell coreceptor complex. Second signaling may be provided to a B cell through its complement receptor 1 (CR1, CD35) or CR2 (CD21). A microbial epitope is bound by the BCR. Complement fragment C3b or C3d also binds to the microbe. CR35 (CR1) binds to the bound C3b and CR21 (CR2) binds to the bound C3d fragment. CD19 and CD81 rapidly associate with the CR. CD19, CD21, and CD81 collectively form the B cell coreceptor complex. Tyrosine kinases (lyn, fyn,Vav, or PI-3K) are activated to phosphorylate ITAMs on Igα and Igβ, allowing Syk docking and the initiation of signaling cascades.

B. T-Dependent activation

Most often, second signals for B cell activation are provided by CD4+ T cells. This is especially true for epitopes found on protein antigens. Engagement of the TCR of a CD4+ T cell and the formation of an immunologic synapse (Fig. 10.17) result from the presentation of pMHC class II by a B cell or APC (first signal). Costimulation through CD28:CD80/86 and/or CD40:CD154 provides a second signal to the T cell, resulting in the production of T cell–derived cytokines such as IL-4. The B cell is signaled through the engagement of the BCR (via Igα and Igβ), costimulatory molecules (e.g., CD40, CD80, and CD86), and the encounter of pMHC class II with the appropriate TCR. These B cell events cause the B cell to express IL-4R. Once the IL-4R encounters its ligand (IL-4), the B cell will proliferate and, in the presence of additional T cell–derived cytokines, differentiate into an antibody-secreting plasma cell.


Figure 10.17

Most B cell responses require CD4+ T cell help. 1. Engagement of pMHC class II with the TCR:CD3:CD4 complex is a first signal to a CD4+ T cell. 2. BCR interaction with its obligate epitope is a first signal to a B cell. CD28 and/or CD154 engagement with CD80/86 and CD40, respectively, provides costimulation to the (3) CD4+ T cell and to (4) the B cell. 5. Interaction of pMHC class II with the αβ TCR and CD4 molecules may provide additional B cell stimulation. Signaling events lead to IL-4 secretion by the T cell and display of IL-4R by the B cell. 

C. Plasma cells and memory B cells

Plasma cells are terminally differentiated B cells (see Chapter 9) that actively secrete immunoglobulins (Fig. 10.18). The epitope specificity of the immunoglobulins secreted by plasma cells is the same as the surface immunoglobulin of the B cell from which it differentiated. Not all B cells differentiate into plasma cells. Following stimulation, some become memory B cells poised for reencounter with the same epitope.


Figure 10.18

Cell interactions leading to antibody secretion.

Chapter Summary

• Dendritic cells sample their environment by phagocytosis and pinocytosis, enzymatically degrade what they ingest, and load the peptide fragments into MHC class II (forming pMHC class II) molecules in a process called antigen presentation.

• Dendritic cells detect threats either directly or indirectly through the same cell surface receptors that are used by the innate immune system.

• Pathogens such as intracellular microbes and viruses bind to cell membranes and directly enter the cytoplasm of the host cell.

• The interface between APC and naïve T cell is called the immunologic synapse. The initial step in building the immunologic synapse is the recognition of pMHC by the TCR. The immunologic synapse both stabilizes T cell-APC interaction and promotes the migration of molecules within the T cell membrane.

• The initial encounter of T cells with antigen is called priming, and the nature of this encounter is crucial to the development of the subsequent adaptive immune response

• Upon activation, antigen-naïve CD4+ Th precursor cells are stimulated to secrete various cytokines, express cell-surface cytokine receptor, and become Th0 cells that are not yet committed to either the Th1 or Th1 pathway.

• Some pathogens, such as viruses, avoid contact with endocytic vesicles entirely by directly entering and replicating within the host cell’s cytoplasm.

• Naïve CD8+ T cells recognize pMHC class I (first signal) displayed on the surface of an infected cell.

• The BCR complex of mature B cells contains membrane-bound IgM and IgD monomers associated with Igα and Igβ molecules. Cross-linking of BCRs initiates signaling.

• BCR binding initiates endocytosis, enzymatic degradation, and subsequent display of peptide fragments as pMHC class II complexes and cause the B cell to express costimulatory molecules, thus allowing the B cell to function as an APC for TCR recognition by a CD4+ T cell and possibly to mature as a plasma cell.

Study Questions

10.1. T cells recognize epitopes they have never before encountered by

A. randomly generating enormous numbers of TCRs prior to antigenic encounter.

B. sampling the environment using phagocytosis and pinocytosis.

C. synthesizing immunoglobulins specific for a wide variety of epitopes.

D. selecting widely expressed molecules as TCR ligands.

E. using genomically encoded pattern recognition receptors.

The correct answer is A. T-cell receptors are randomly generated prior to any engagement with antigens. Phagocytic cells use phagocytosis and pinocytosis to internalize antigens without regard to the specificity of the ingested material. T cells do not synthesize immunoglobulins. The selection for receptors recognizing a widely expressed set of microbial molecules is a property of toll-like receptors, not of T-cell receptors. The genomically encoded pattern recognition receptors are toll-like receptors.

10.2. Which of the following naïve cells load peptide fragments into MHC class II molecules?

A. CD4+ T cells

B. CD8+ T cells

C. dendritic cells

D. γδ T cells

E. neutrophils

The correct answer is C. Of those cell types listed, only dendritic cells can process peptide fragments and load them on MHC II molecules for presentation. Lymphocytes, whether of the CD4+, CD8+, or γδ type, cannot do this. Neutrophils can ingest peptides and degrade them but do not synthesize MHC II molecules.

10.3. Fragments of a cytoplasmic pathogen are presented to T cells by

A. direct engagement of cell surface pattern recognition receptors.

B. macropinocytosis into γδ T cells.

C. MHC class I molecules to CD8+ T cells.

D. phagocytosis and presentation to CD4+ T cells.

E. placement into endocytic vesicles and complexing with MHC class II molecules.

The correct answer is C. Cytoplasmically derived peptides are presented by MHC I molecules. Pattern recognition receptors do not present peptides to T cells nor do γδ T cells. CD8+ T cells recognize peptide fragments presented by class I MHC molecules. They are not processed in endocytic vesicles for presentation by MHC II molecules to CD4+ T cells.

10.4. The term immunologic synapse refers to

A. PAMP recognition by pattern recognition receptors.

B. restriction of CD4+ T cells to MHC class I.

C. selective unresponsiveness of T cells.

D. T cell recognition of soluble molecules.

E. the interface between antigen-presenting cells and T cells.

The correct answer is E. The immunologic synapse is the interface between T cells and antigen-presenting cells. It does not refer to the recognition and binding by pattern recognition receptors. CD4+ T cells are restricted to the recognition of peptide presented by MHC II molecules. The selective unresponsiveness of T cells is called tolerance or anergy. T-cell receptors do not recognize soluble molecules.

10.5. CD4+ T cells that respond to intracellular pathogens by recruiting and activating phagocytic cells are termed

A. antigen-presenting cells.

B. cytotoxic T lymphocytes.

C. Th0 cells.

D. Th1 cells.

E. Th2 cells.

The correct answer is D. CD4+ Th1 cells recruit and activate macrophages to destroy intracellular pathogens. Antigen-presenting cells are not T cells. Cytotoxic T lymphocytes are CD8+. Th0 and Th2 cells, although also being CD4+, do not engage in this activity.

10.6. In the presence of microbe-derived lipopolysaccharide,

A. antigen-presenting cells may secrete IL-12.

B. release of cytokines results in leukocyte activation.

C. stimulation of IFN-γ secretion activates leukocytes.

D. Th0 cells further differentiate into Th1 cells.

E. all of the above

The correct answer is E. All of these activities can follow activation of phagocytic cells by the recognition and binding of lipopolysaccharide via their toll-like receptors. Activated phagocytes can secrete various cytokines that can be involved in chemotaxis and activation of other leukocytes. Among these cytokinesis IL-12, which stimulates natural killer cells to increase their production of IFN-γ, which, in turn, promotes the differentiation of CD4+ Th0 cells into Th1 cells.

10.7. Upon encountering an appropriate pMHC I on an infected cell,

A. B-cell receptors become cross-linked and signaling ensues.

B. CD4+ cells release IL-4.

C. CD8+ cytotoxic T cells destroy the infected cell.

D. naïve Th1 cells secrete cytokines.

E. Th0 cells differentiate into Th2 cells.

The correct answer is C. Once activated, cytotoxic T lymphocytes can bind and destroy infected cells expressing pMHC I complexes recognized by their T-cell receptors. Neither B cells nor CD4+ T cells recognize pMHC I. T helper cells—whether Th0, Th1, or Th2—are CD4+ and do not recognize pMHC I.

10.8. Activation of an individual naïve B cell involves binding of membrane-associated epitopes leading to

A. dendritic cell presentation of MHC class I.

B. recognition of different epitopes by surface IgD and IgM.

C. signaling from both the B-cell receptor and a CD4+ Th2 cell.

D. the isotype switch.

E. ubiquitination and destruction of antigen by proteasomes.

The correct answer is C. Activation of a naïve B cell requires both the engagement of its B-cell receptor (immunoglobulin) and the receipt of secondary signals from CD4+ Th2 cells. The B cell does not require interaction with antigen-presenting cells such as dendritic cells. The IgD and IgM on its surface have the same epitope specificity. Turn over of cytoplasmic molecules by proteasomes is a normal on going activity but is not involved in the naïve B cell’s activation. The isotype switch occurs only during the reactivation of memory B cells, not during the initial activation of naïve B cells.