Comprehensive Physiology Wiley Online Library

Cellular Immunology

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Overview
1.1 The Adaptive Immune System Combats Intracellular and Extracellular Pathogens
1.2 The Antigen‐Specific Receptors on B and T Lymphocytes Bind Distinct Ligands
1.3 MHC Class I and II Molecules Present Antigens to CD8+ and CD4+ T Cells, Respectively
1.4 The Clonal Selection Theory of Acquired Immunity Provides a Mechanism for Immunologic Specificity and Memory
1.5 Lymphocytes Require Two Signals for Activation to Effector Function
1.6 Summary
2 Members of the Immunoglobulin Superfamily
2.1 Immunoglobulins
2.2 T Cell Receptor Structure, Genes, and the Generation of T Cell Receptor Diversity
2.3 Major Histocompatibility Complex (MHC) Molecules
3 Lymphocyte Development
3.1 Monoclonal Antibodies and Flow Cytometry Facilitate the Identification of Distinct Lymphocyte Subpopulations
3.2 B Cell Development
3.3 T Cell Development
4 Peripheral Lymphoid Organs and Lymphocyte Circulation
5 Lymphocyte Activation
5.1 Antigen Processing and Presentation: The Generation of Signal 1
5.2 T Cell Activation
5.3 8 Cell Activation
6 T Cell Effector Functions
6.1 Cytokine Secretion
6.2 Delayed‐Type Hypersensitivity (DTH)
6.3 Cytolysis
6.4 Control of T Cell Effector Functions
7 Immunological Memory
7.1 B Cells: Somatic Mutation, Affinity Maturation, and Memory
7.2 T Cell Memory
8 Immunological Tolerance
9 Immunological Self/Nonself Discrimination
10 Future Directions
Figure 1. Figure 1.

Humoral immunity and cellular immunity. When pathogen invades the body, immune system responds with three types of reaction. Cells of humoral system (B cells) secrete antibodies that can bind to pathogen. Cells of cellular system (T cells) carry out two major types of functions. CD8+ T cells develop ability to kill pathogen‐infected cells. CD4+ helper T cells, responding to pathogen, secrete protein factors (lymphokines) that stimulate body's overall response.

Figure and legend adapted from Darnell et al. with permission from the publisher
Figure 2. Figure 2.

Organization and translocation of IgH genes. Immunoglobulin H chains are encoded by four distinct genetic elements—Igh‐V (V), Igh‐D (D), Igh‐J (J), and Igh‐C (C) genes. V, D, and J genes together specify variable region of H chain. IgH‐C gene specifies C region. Same V region can be found in association with each of C regions (for example, μ, δ, γ3, γ1, γ2b, γ2a, ε, and α). In germline genome, V, D, and J genes are far apart and there are multiple forms of each of these genes. In course of lymphocyte development, VDJ gene complex is formed by translocation of individual V and D genes so that they lie next to one of the J genes, with excision of intervening genes. This VDJ complex is initially expressed with m and d C genes but may subsequently be translocated so that it lies near one of other C genes (for example, α) and in that case leads to expression of VDJα chain.

Figure and legend from Paul with permission from the publisher
Figure 3. Figure 3.

Antigenic determinants (epitopes). Antigenic determinants in proteins (shown as thick lines) may depend on protein conformation as well as upon covalent structure. Some linear determinants are accessible in native proteins, whereas others are exposed only upon denaturation.

Figure and text adapted from Abbas et al. with permission from the publisher
Figure 4. Figure 4.

Pathways of antigen processing and presentation. Cytoplasmic antigens (Ca) are degraded in cytoplasm and then enter rough endoplasmic reticulum (RER) through peptide transporter. In RER, Ca‐derived peptides are loaded into class I MHC molecules that move through Golgi apparatus into secretory vesicles and are then expressed on cell surface, where they may be recognized by CD8+ T cells. Exogenous antigen (Ea) enters cell through endocytosis and is transported from early endosomes into late endosomes or pre‐lysosomes, where it is fragmented and where peptide resulting from it (Ea‐derived peptide) is loaded into class II MHC molecules. Latter have been transported from RER through Golgi apparatus to peptide‐containing vesicles. Class II MHC molecule‐Ea‐derived peptide complexes are then transported to cell surface where they may be recognized by CD4+ T cells.

Figure and legend from Paul with permission
Figure 5. Figure 5.

Receptor‐ligand interactions involved in T cell recognition of conventional antigens and superantigens. Peptide fragments (pep) of protein antigens are held in a groove on membrane‐distal aspect of MHC molecules on APCs; peptide‐binding groove and adjacent α‐helices (αh) form polymorphic region of MHC molecules. During T‐APC interaction, MHC‐bound peptides and flanking MHC α‐helices come into contact with hypervariable region of T‐cell receptor (TCR); this region is product of variable (V), diversity (D), and joining (J) gene segments which rearrange during T cell ontogeny. Superantigens, which can be either soluble or cell bound, cause T cells and APCs to stick together by adhering to sides of MHC and TCR molecules; these regions of MHC and TCR molecules are relatively nonpolymorphic, which means superantigens are immunogenic for very high proportion of T cells. For recognition of both conventional antigens and superantigens, T‐APC interaction is strengthened by binding of CD4 or CD8 molecules to nonpolymorphic sites on MHC molecules. These “co‐receptor” molecules also play a role in T‐cell triggering.

Figure and legend reproduced from Sprent with permission
Figure 6. Figure 6.

Simple experiment demonstrates three cardinal features of adaptive immune system: specificity, memory, and self‐tolerance. See text for details.

Figure 7. Figure 7.

Clonal selection theory of acquired immunity. Each antigen (A or B) selects preexisting clone of specific lymphocytes and stimulates its proliferation and differentiation. Diagram shows only B lymphocytes giving rise to antibody‐secreting cells and memory cells, but same principle applies to T lymphocytes as well.

Figure and text adapted from Abbas et al. with permission
Figure 8. Figure 8.

A. Schematic representation of IgG molecule, with presence of variable and constant region domains indicated as light and dark bars, respectively. Note presence of hypervariable regions within V regions of both heavy and light chains, and division of the Ig molecule into antigen‐binding and biologic effector regions. B. Schematic drawing of V‐ and C‐region domains of antibody light chain. Each domain contains two β‐pleated sheets containing three and four β strands (indicated by white and shaded arrows), and intrachain disulfide bonds linking opposing sheets are presented as black bars. Amino acids are numbered from amino terminus, with loops containing amino acids 96, 26, and 53 making up three hypervariable regions responsible for antigen binding.

From Wasserman and Capra with permission. From Edmundson et al. with permission
Figure 9. Figure 9.

Molecules involved in lymphocyte recognition and activation. With exception of ζ and η, molecules all show sequence homology with Ig molecules and are viewed as part of a single family, the immunoglobulin (Ig) superfamily; these molecules probably arose by gene duplication and divergence from common primordial single domain structure. Circles in figure signify domains (predicted from primary sequences); V and C domains show homology with IgV and IgC domains, respectively; based on sequence homology, C domains fall into two broad groups, C1 and C2.

Figure adapted from Hunkapiller and Hood with permission. Text adapted from Paul with permission
Figure 10. Figure 10.

Structure of major histocompatibility class 1 molecule. A. Schematic of human MHC class 1 molecule, HLA‐A2. Heavy chain has three domains, with polymorphic α1 and α2 domains contributing to peptide‐binding site and nonpolymorphic α3 domain responsible for binding CD8 co‐receptor molecule. B. Pockets in peptide‐binding site of class 1. Pockets are labeled A to F. Residues in peptide occupying or interacting with pockets are shown as P1 to P9. P4 and P5 are above the plane in the top part of the figure. The lower part of the figure shows a side view of the binding site. The side chains of P2, P3, P6, and P9 face into the groove and are not available for interaction with the T cell receptor. Side chains of PI, P4, and P5 protrude out of the groove and are available for recognition. Pockets A and F contain conserved residues that interact with the free amino and carboxyl termini of the peptide; pockets B to E are more variable among alleles.

From Bjorkman et al with permission. Figure from Matsumura et al with permission. Text from Germain with permission
Figure 11. Figure 11.

Linear map of H‐2 complex. Map units measured in centimorgans were determined by recombination frequencies between indicated loci. T, brachyury; tf, tufted; GLO, glyoxalase; Tla, thymus leukemia antigen; thf, thin fur.

Text and figure from Hansen et al. with permission from the publisher
Figure 12. Figure 12.

Production of hybridomas. Steps in derivation of hybridomas can be outlined as shown. Spleen cells from immunized donors are fused with myeloma cells bearing selection marker. Fused cells are then cultured in selective medium until visible colonies grow, and their supernatants are then screened for antibody production.

Figure and legend from Berzofsky et al. with permission from publisher
Figure 13. Figure 13.

Schematic of a two‐laser fluorescence‐activated cell sorter, containing fluid, mechanical, and optical elements. See text for detains.

Figure and legend adapted from Parks et al. with permission from the publisher
Figure 14. Figure 14.

T cell selection in thymus. CD4 8 stem cells under capsule of thymus spawn huge numbers of CD4+ 8+ immature T cells expressing low density of ab TcR molecules. Small proportion of these cells are capable of binding MHC class I or II molecules displayed on cortical epithelium. These T cells are positively selected: Selected cells up‐regulate TcR expression, down‐regulate expression of one of accessory molecules (CD4 or CD8), and move to medulla, where they appear as typical CD4+ or CD8+ mature T cells. Some of these cells have high affinity for self‐MHC molecules and die when T cells pass through dense network of APCs (macrophages and dendritic cells) and epithelial cells in medulla; some deletion of cells can also occur in cortex through contact with cortical epithelium. Only very small proportion (1%–2%) of total thymocytes are exported from thymus; vast majority fail either positive or negative selection steps.

Figure and legend adapted from Sprent with permission
Figure 15. Figure 15.

Schematic diagram of lymph node, showing distinct cortex with lymphoid follicles and dense lymphocytes and medulla with lymphatic cords and vessels.

Figure and text from Abbas et al. with permission
Figure 16. Figure 16.

T cell antigen receptor complex. Illustrated schematically is antigen‐binding subunit comprising αβ heterodimer, Ti, and associated invariant CD3 and ζ chains. Acidic (−) and basic (+) residues located within plasma membrane are indicated. Open rectangular boxes indicate motifs within cytoplasmic domains that interact with cytoplasmic protein tyrosine kinases.

Figure and legend from Weiss with permission of the publisher
Figure 17. Figure 17.

Intracellular events following ligation of T cell receptor for antigen. APC, antigen‐presenting cell; IL‐2, interleukin‐2; PLCg1, phospholipase Cg1; PIP2, phosphatidylinositol bisphosphate; IP3, inositol 1,4,5‐triphosphate; DAG, diacylglycerol; PKC, protein kinase C; NF‐ATc, cytoplasmic component of nuclear factor of activated T cells; NF‐kb, nuclear factor of k‐chain gene enhancer; ARRE, antigen‐receptor response element; CD28RC, CD28 response complex; CD28RE, CD28 response element; TRE, TPA (phorbol ester) response element; OBM, octamer‐binding motif; Oct 1, octamer binding protein 1. See text for details.

Figure from Schwarz with permission
Figure 18. Figure 18.

Cytokines generated by cells of innate immune response drive CD4+ Th cell subset differentiation. Pathogens and their products interact with several components of innate immune system, including macrophages, NK cells, γδ T cells, and/or basophils/mast cells. Some pathogens (quite frequently bacteria, protozoa, and viruses) interact with macrophages, stimulating production of IL‐12, enhancing IFN‐γ production by NK cells and/or γδ T cells, and promoting differentiation of naive Th cells towards the Th1 cell phenotype. Other pathogens (frequently helminths) stimulate cells to produce IL‐4 that drives Th2 cell differentiation. The cells producing IL‐4 during early stages of infection have not been defined but could include basophils or mast cells, γδ T cells, or undefined cell population. All of in vitro models suggest that most efficient APCs are dendritic cells.

Figure and legend from Scott with permission


Figure 1.

Humoral immunity and cellular immunity. When pathogen invades the body, immune system responds with three types of reaction. Cells of humoral system (B cells) secrete antibodies that can bind to pathogen. Cells of cellular system (T cells) carry out two major types of functions. CD8+ T cells develop ability to kill pathogen‐infected cells. CD4+ helper T cells, responding to pathogen, secrete protein factors (lymphokines) that stimulate body's overall response.

Figure and legend adapted from Darnell et al. with permission from the publisher


Figure 2.

Organization and translocation of IgH genes. Immunoglobulin H chains are encoded by four distinct genetic elements—Igh‐V (V), Igh‐D (D), Igh‐J (J), and Igh‐C (C) genes. V, D, and J genes together specify variable region of H chain. IgH‐C gene specifies C region. Same V region can be found in association with each of C regions (for example, μ, δ, γ3, γ1, γ2b, γ2a, ε, and α). In germline genome, V, D, and J genes are far apart and there are multiple forms of each of these genes. In course of lymphocyte development, VDJ gene complex is formed by translocation of individual V and D genes so that they lie next to one of the J genes, with excision of intervening genes. This VDJ complex is initially expressed with m and d C genes but may subsequently be translocated so that it lies near one of other C genes (for example, α) and in that case leads to expression of VDJα chain.

Figure and legend from Paul with permission from the publisher


Figure 3.

Antigenic determinants (epitopes). Antigenic determinants in proteins (shown as thick lines) may depend on protein conformation as well as upon covalent structure. Some linear determinants are accessible in native proteins, whereas others are exposed only upon denaturation.

Figure and text adapted from Abbas et al. with permission from the publisher


Figure 4.

Pathways of antigen processing and presentation. Cytoplasmic antigens (Ca) are degraded in cytoplasm and then enter rough endoplasmic reticulum (RER) through peptide transporter. In RER, Ca‐derived peptides are loaded into class I MHC molecules that move through Golgi apparatus into secretory vesicles and are then expressed on cell surface, where they may be recognized by CD8+ T cells. Exogenous antigen (Ea) enters cell through endocytosis and is transported from early endosomes into late endosomes or pre‐lysosomes, where it is fragmented and where peptide resulting from it (Ea‐derived peptide) is loaded into class II MHC molecules. Latter have been transported from RER through Golgi apparatus to peptide‐containing vesicles. Class II MHC molecule‐Ea‐derived peptide complexes are then transported to cell surface where they may be recognized by CD4+ T cells.

Figure and legend from Paul with permission


Figure 5.

Receptor‐ligand interactions involved in T cell recognition of conventional antigens and superantigens. Peptide fragments (pep) of protein antigens are held in a groove on membrane‐distal aspect of MHC molecules on APCs; peptide‐binding groove and adjacent α‐helices (αh) form polymorphic region of MHC molecules. During T‐APC interaction, MHC‐bound peptides and flanking MHC α‐helices come into contact with hypervariable region of T‐cell receptor (TCR); this region is product of variable (V), diversity (D), and joining (J) gene segments which rearrange during T cell ontogeny. Superantigens, which can be either soluble or cell bound, cause T cells and APCs to stick together by adhering to sides of MHC and TCR molecules; these regions of MHC and TCR molecules are relatively nonpolymorphic, which means superantigens are immunogenic for very high proportion of T cells. For recognition of both conventional antigens and superantigens, T‐APC interaction is strengthened by binding of CD4 or CD8 molecules to nonpolymorphic sites on MHC molecules. These “co‐receptor” molecules also play a role in T‐cell triggering.

Figure and legend reproduced from Sprent with permission


Figure 6.

Simple experiment demonstrates three cardinal features of adaptive immune system: specificity, memory, and self‐tolerance. See text for details.



Figure 7.

Clonal selection theory of acquired immunity. Each antigen (A or B) selects preexisting clone of specific lymphocytes and stimulates its proliferation and differentiation. Diagram shows only B lymphocytes giving rise to antibody‐secreting cells and memory cells, but same principle applies to T lymphocytes as well.

Figure and text adapted from Abbas et al. with permission


Figure 8.

A. Schematic representation of IgG molecule, with presence of variable and constant region domains indicated as light and dark bars, respectively. Note presence of hypervariable regions within V regions of both heavy and light chains, and division of the Ig molecule into antigen‐binding and biologic effector regions. B. Schematic drawing of V‐ and C‐region domains of antibody light chain. Each domain contains two β‐pleated sheets containing three and four β strands (indicated by white and shaded arrows), and intrachain disulfide bonds linking opposing sheets are presented as black bars. Amino acids are numbered from amino terminus, with loops containing amino acids 96, 26, and 53 making up three hypervariable regions responsible for antigen binding.

From Wasserman and Capra with permission. From Edmundson et al. with permission


Figure 9.

Molecules involved in lymphocyte recognition and activation. With exception of ζ and η, molecules all show sequence homology with Ig molecules and are viewed as part of a single family, the immunoglobulin (Ig) superfamily; these molecules probably arose by gene duplication and divergence from common primordial single domain structure. Circles in figure signify domains (predicted from primary sequences); V and C domains show homology with IgV and IgC domains, respectively; based on sequence homology, C domains fall into two broad groups, C1 and C2.

Figure adapted from Hunkapiller and Hood with permission. Text adapted from Paul with permission


Figure 10.

Structure of major histocompatibility class 1 molecule. A. Schematic of human MHC class 1 molecule, HLA‐A2. Heavy chain has three domains, with polymorphic α1 and α2 domains contributing to peptide‐binding site and nonpolymorphic α3 domain responsible for binding CD8 co‐receptor molecule. B. Pockets in peptide‐binding site of class 1. Pockets are labeled A to F. Residues in peptide occupying or interacting with pockets are shown as P1 to P9. P4 and P5 are above the plane in the top part of the figure. The lower part of the figure shows a side view of the binding site. The side chains of P2, P3, P6, and P9 face into the groove and are not available for interaction with the T cell receptor. Side chains of PI, P4, and P5 protrude out of the groove and are available for recognition. Pockets A and F contain conserved residues that interact with the free amino and carboxyl termini of the peptide; pockets B to E are more variable among alleles.

From Bjorkman et al with permission. Figure from Matsumura et al with permission. Text from Germain with permission


Figure 11.

Linear map of H‐2 complex. Map units measured in centimorgans were determined by recombination frequencies between indicated loci. T, brachyury; tf, tufted; GLO, glyoxalase; Tla, thymus leukemia antigen; thf, thin fur.

Text and figure from Hansen et al. with permission from the publisher


Figure 12.

Production of hybridomas. Steps in derivation of hybridomas can be outlined as shown. Spleen cells from immunized donors are fused with myeloma cells bearing selection marker. Fused cells are then cultured in selective medium until visible colonies grow, and their supernatants are then screened for antibody production.

Figure and legend from Berzofsky et al. with permission from publisher


Figure 13.

Schematic of a two‐laser fluorescence‐activated cell sorter, containing fluid, mechanical, and optical elements. See text for detains.

Figure and legend adapted from Parks et al. with permission from the publisher


Figure 14.

T cell selection in thymus. CD4 8 stem cells under capsule of thymus spawn huge numbers of CD4+ 8+ immature T cells expressing low density of ab TcR molecules. Small proportion of these cells are capable of binding MHC class I or II molecules displayed on cortical epithelium. These T cells are positively selected: Selected cells up‐regulate TcR expression, down‐regulate expression of one of accessory molecules (CD4 or CD8), and move to medulla, where they appear as typical CD4+ or CD8+ mature T cells. Some of these cells have high affinity for self‐MHC molecules and die when T cells pass through dense network of APCs (macrophages and dendritic cells) and epithelial cells in medulla; some deletion of cells can also occur in cortex through contact with cortical epithelium. Only very small proportion (1%–2%) of total thymocytes are exported from thymus; vast majority fail either positive or negative selection steps.

Figure and legend adapted from Sprent with permission


Figure 15.

Schematic diagram of lymph node, showing distinct cortex with lymphoid follicles and dense lymphocytes and medulla with lymphatic cords and vessels.

Figure and text from Abbas et al. with permission


Figure 16.

T cell antigen receptor complex. Illustrated schematically is antigen‐binding subunit comprising αβ heterodimer, Ti, and associated invariant CD3 and ζ chains. Acidic (−) and basic (+) residues located within plasma membrane are indicated. Open rectangular boxes indicate motifs within cytoplasmic domains that interact with cytoplasmic protein tyrosine kinases.

Figure and legend from Weiss with permission of the publisher


Figure 17.

Intracellular events following ligation of T cell receptor for antigen. APC, antigen‐presenting cell; IL‐2, interleukin‐2; PLCg1, phospholipase Cg1; PIP2, phosphatidylinositol bisphosphate; IP3, inositol 1,4,5‐triphosphate; DAG, diacylglycerol; PKC, protein kinase C; NF‐ATc, cytoplasmic component of nuclear factor of activated T cells; NF‐kb, nuclear factor of k‐chain gene enhancer; ARRE, antigen‐receptor response element; CD28RC, CD28 response complex; CD28RE, CD28 response element; TRE, TPA (phorbol ester) response element; OBM, octamer‐binding motif; Oct 1, octamer binding protein 1. See text for details.

Figure from Schwarz with permission


Figure 18.

Cytokines generated by cells of innate immune response drive CD4+ Th cell subset differentiation. Pathogens and their products interact with several components of innate immune system, including macrophages, NK cells, γδ T cells, and/or basophils/mast cells. Some pathogens (quite frequently bacteria, protozoa, and viruses) interact with macrophages, stimulating production of IL‐12, enhancing IFN‐γ production by NK cells and/or γδ T cells, and promoting differentiation of naive Th cells towards the Th1 cell phenotype. Other pathogens (frequently helminths) stimulate cells to produce IL‐4 that drives Th2 cell differentiation. The cells producing IL‐4 during early stages of infection have not been defined but could include basophils or mast cells, γδ T cells, or undefined cell population. All of in vitro models suggest that most efficient APCs are dendritic cells.

Figure and legend from Scott with permission
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Ephraim Fuchs. Cellular Immunology. Compr Physiol 2011, Supplement 31: Handbook of Physiology, Cell Physiology: 743-785. First published in print 1997. doi: 10.1002/cphy.cp140119