Page 60 phocytes or dendritic cells, appear to serve as APC in an immunologically naive individual (see later in this chapter). 3. Antigen processing is a complex sequence of events that involves endocytosis of membrane patches with attached organisms or proteins, and transport to an acidic compartment (lysosome) within the cell which allows for the breakdown of the engulfed material into small fragments. In the case of a microorganism, processing involves the breakdown of the infectious agent and the generation of immunogenic fragments. In the case of complex proteins, processing involves unfolding and breakdown into small peptides. 4. Antigen presentation to T-lymphocytes requires the assembly on MHC-II-peptide complexes and their transport to the cell membrane. As complex immunogens are broken down, vesicles coated with newly synthesized HLA-II molecules fuse with the lysosome. Some of the peptides generated during processing have affinity for the binding site located within the MHC-II α / β heterodimer. Once bound, these peptides seem protected against further degradation and the MHC-II-peptide complexes are transported to the cell membrane (Fig. 4.6). D. Activation of Helper T Lymphocytes. The activation of resting T helper cells requires a complex sequence of signals. Of all the signals involved, the only antigen-specific signal is the recognition by the T- cell receptor (TcR) of the complex formed by an antigen-derived peptide and an MHC-II molecule expressed on the membrane of an APC. 1. The role of APC goes well beyond that of a site for generation and expression of antigen fragments of adequate size. The interaction between APC and helper T lymphocytes is essential for T-cell stimulation, because the binding of the antigen-derived peptide to the binding site of the TcR is of low affinity, and other receptor-ligand interactions are required to maintain T-lymphocyte adhesion to APC and for the delivery of required co- stimulatory signals. 2. The TCR on a helper T lymphocyte interacts with both the antigen-derived peptide and the MHC-II molecule. This selectivity of the TcR from helper T lymphocytes to interact with MHC-II molecules results from the fact that, during ontogeny, the differentiation of helper and cytotoxic T lymphocytes is based on the ability of their TcR to interact, respectively, with MHC-II molecules (helper T lymphocytes) or with MHC-I molecules (cytotoxic T lymphocytes) (see Chapter 10). The interactions between T lymphocytes and MHC-expressing cells are strengthened by special molecules on the lymphocyte membrane which also interact with MHC molecules: the CD4 molecule on helper T cells interacts with MHC-II molecules, and the CD8 molecule on cytotoxic lymphocytes interacts with MHC-I molecules. 3. Several other cell adhesion molecules (CAM) can mediate lymphocyte- APC interactions, including lymphocyte function-associated antigen (LFA)-1 interacting with the intercellular adhesion molecules (ICAM)-1, -2 and -3, and CD2 interacting with CD58 (LFA-3). All interactions other than the one between the MHC-associated peptide and the TcR are not antigen specific (i.e., they mediate adhesion between T lymphocytes and APC). 4. Accessory cells participate in the activation of helper T lymphocytes through the delivery of signals involving cell-cell contact as well as by the release of soluble factors, such as interleukin-1 and interleukin-12. Page 61 Figure 4.6 Diagrammatic representation of the general steps in antigen processing. The antigen is ingested, partially degraded, and, after vesicles coated with nascent MHC-II proteins fuse with the phagolysosomes, antigen-derived polypeptides bind to the MHC-II molecule. In this bound form, the oligopeptides seem protected against further denaturation and are transported together with the MHC-II molecule to the cell membrane, where they will be presented to CD4+ T lymphocytes in traffic through the tissue where the APC are located. 5. Given the predominance of nonspecific signals, what ensures that the activated lymphocytes are predominantly those involved in an antigen-specific response? a. An essential and first activation signal is delivered through the antigen-specific TcR. The signal is dependent upon appropriate binding of the TcR-bearing helper T lymphocyte and an APC presenting an antigen-derived peptide properly associated to an MHC-II molecule. b. One consequence of the activating signal is the up-regulation and modification of several membrane proteins on the T -cell membrane, such as CD2, CD28, CD40 ligand (CD40L, CD154, gp39), LFA-1 and ICAM-1. These molecules have counterparts on the APC: CD58 (LFA-3), CD80/86, CD40, ICAM-1, and LFA-1 (ICAM-1 and LFA-1 are expressed in both cell populations and interact with each other). The interactions involving these molecules contribute both to establishing intimate cell-cell contact and to delivering additional activating signals to T cells. Page 62 c. In addition, APC produce cytokines such as interleukin-1 (IL-1), which promotes growth and differentiation of many cells types, including T and B lymphocytes. Both membrane-bound and soluble IL-1 have been shown to be important in activating T lymphocytes in vitro. Membrane-bound IL-1 can only activate T lymphocytes in close contact with the APC. d. Thus, only helper T lymphocytes specifically recognizing the MHC-II-associated peptide undergo the changes that facilitate cell-cell contact and signaling, and that ensures their specific proliferation and differentiation. 6. The precise sequence of intracellular events resulting in T-cell proliferation and differentiation will be discussed in greater detail in Chapter 11. The following are the major steps in the activation sequence: a. The occupancy of the TcR signals the cell through a closely associated complex of molecules, known as CD3, which has signal-transducing properties. b. Co-stimulatory signals are delivered by CD4, as a consequence of the interaction with MHC-II, and by CD45, a tyrosine phosphatase, whose mechanism of activation has not yet been defined. c. The activation of CD45 initiates the sequential activation of several protein kinases closely associated with CD3 and CD4. The activation of the kinase cascade has several effects, namely: i. Increased expression of cell adhesion molecules, allowing additional signaling of the T lymphocyte. ii. Phospholipase C activation, leading to the mobilization of Ca 2+ - dependent second messenger systems, such as the one involving inositol triphosphate (IP 3 ), which promotes an increase in intracellular free Ca 2+ released from intracellular organelles and taken up through the cell membrane. The increase in intracellular free calcium results in activation of a serine threonine phosphatase known as calcineurin. iii. Diacylglycerol (DAG), another product released by phospholipase C, activates protein kinase C (PKC), and, consequently, other enzymes are activated in a cascading sequence. iv. The activation of second messenger systems results in the activation and translocation of nuclear binding proteins, such as the nuclear factor-kappa B (NF- κ B) and the nuclear factor of activated T cells (NF-AT). Once translocated to the nucleus, these factors induce genes controlling T-cell proliferation, such as those encoding interleukin-2 (IL-2), the IL-2 receptor gene, and c-myc. d. The binding of IL-2 to its receptor triggers an additional activation pathway involving nuclear binding proteins that promote the entry of the cell into a division cycle. This activation pathway seems to promote primarily the proliferation of helper T cells, which assist the differentiation of B cells and of cytotoxic T cells. Page 63 E. Antigen Presentation and Activation of Cytotoxic T Lymphocytes. As mentioned in Chapter 3, cytotoxic T lymphocytes can be sensitized to react against virus-derived peptides embedded in self MHC-1 molecules expressed by virus-infected cells. The infected cell acts as an APC by expressing viral peptides complexed with their own MHC -I molecules. The way in which MHC-I molecules and viral peptides become associated has been recently elucidated (Fig. 4.7). Figure 4.7 Diagrammatic representation of the general steps involved in the presentation of virus derived peptides on the membrane of virus-infected cells. The virus binds to membrane receptors and is endocytosed, its outer coats are digested, and the viral genome (in this case DNA) is released into the cytoplasm. Once released, the viral DNA diffuses back into the nucleus where it is initially transcribed into mRNA by the cell's polymerases. The viral mRNA is translated into proteins that diffuse into the cytoplasm, where some will be broken down into oligopeptides. These small peptides are transported back into the endoplasmic reticulum where they associate with newly synthesized MHC-I molecules. The MHC-I/oligopeptide complex becomes associated to a second transport protein and is eventually inserted into the cell membrane. In the cell membrane, it can be presented to CD8+ T lymphocytes in traffic through the tissue where the virus-infected cell is located. A similar mechanism would allow an MHC-II synthesizing cell to present MHC-II/oligopeptide complexes to CD4+ lymphocytes. Page 64 1. When a virus infects a cell, it takes over the cell's synthetic machinery to produce its own proteins. In the early stages of infection, the cell will produce both is own proteins and viral proteins. Some of the nascent viral proteins diffuse into the cytoplasm where they become associated with degradative enzymes forming a peptide-enzyme complex (proteasome). In these complexes, the viral protein is partially digested, and the resulting peptides bind to transport proteins (TAP, transport- associated proteins), which deliver them to the endoplasmic reticulum, where MHC-I molecules are being synthesized. 2. In the endoplasmic reticulum, the viral peptides bind to newly synthesized MHC-class I molecules, and the resulting MHC-viral peptide complex is transported to the infected cell's membrane. 3. Among resting, circulating cytotoxic T lymphocytes, some carry antigen receptors able to recognize associations of MHC-I and non-self peptides; occupancy of the binding site on the TcR by MHC-I-associated peptide provides the antigen-specific signal that drives cytotoxic T cells. 4. Cytotoxic T lymphocytes also differentiate and proliferate when mixed with T lymphocytes from a different individual in vitro (mixed lymphocyte reaction) or when encountering cells from an individual of the same species but from a different genetic background, as a consequence of tissue or organ transplantation. 5. Similar to helper T cells, the stimulation of cytotoxic T cells also requires additional signals and interactions, some of which depend upon cell-cell contact, such as those mediated by the interaction of CD8 with MHC-I, CD2 with CD58 (LFA-3), LFA-1 with ICAM family members, and CD28 with CD80 and CD86, to name a few. 6. The expansion of antigen-activated cytotoxic T lymphocytes requires the secretion of IL-2. Rarely, activated cytotoxic T lymphocytes can secrete sufficient quantities of IL-2 to support their proliferation and differentiation, and thus proceed without help from other T-cell subpopulations. 7. Activated helper T lymphocytes may also provide the IL-2 necessary for cytotoxic T- lymphocyte differentiation, but their activation requires the presentation of antigen-derived peptides in association with MHC-II molecules. a. In the case of antiviral responses, virus-infected macrophages are likely to express viral peptide-MHC-II complexes on their membrane; these complexes are able to activate CD4 + helper T cells. b. In the case of mixed lymphocyte reactions, T cells recognize non-self peptides bound to MHC-II molecules, which are either shared between the two cell populations, or sufficiently alike to allow the stimulatory interaction. MHC-II-expressing cells have to be present for the reaction to take place. i. Naive helper T lymphocytes interact with non-self peptide-MHC-II complexes, while cytotoxic T lymphocytes are activated through the recognition of non-self peptide-MHC-I complexes. ii. The absolute requirement for MHC-II-expressing cells suggests that activation of helper T cells is essential for the differentiation of cytotoxic CD8 + cells. This reflects the requirement for helper T Page 65 cells to provide cytokines and probably other co-stimulatory signals essential for cytotoxic T-cell growth and differentiation. F. Antigen Presentation and Activation of B Lymphocytes. In contrast to T lymphocytes, B lymphocytes recognize external epitopes of unprocessed antigens, which do not have to be associated to MHC molecules. 1. Some special types of APC, such as the Langerhans cells of the epidermis and the dendritic cells of the germinal centers, appear to adsorb complex antigens to their membranes, may be able to maintain them in that form for long periods of time, and may be able to present the antigen to B lymphocytes for as long as it remains adsorbed. 2. Additional signals necessary for B-cell activation, proliferation, and differentiation are provided by accessory cells and helper T lymphocytes. A major role is believed to be played by a complex of four proteins associated noncovalently with the membrane immunoglobulin, including CD19 and CD21. These proteins seem to play a role similar to CD4 or CD8 in T lymphocytes, potentiating the signal delivered through occupancy of the binding site on membrane immunoglobulin. 3. Similar to the TcR, membrane immunoglobulins have short intracytoplasmic domains, which do not appear to be involved in signal transmission. At least two heterodimers composed of two different polypeptide chains, termed Ig α and Ig β , with long intracytoplasmic segments are associated to each membrane immunoglobulin. These heterodimers seem to have a dual function: a. They act as transport proteins, capturing nascent immunoglobulin molecules in the endoplasmic reticulum and transporting them to the cell membrane. b. They are believed to be the “docking sites” for a family of protein kinases related to the src gene product, including p56 lck and p59 fyn , which also play a role in T-cell activation. Another parallel with T- cell activation lies in the essential role of the phosphatase CD45 for p56 lck activation, thus initiating a cascade of tyrosine kinase activation. Specific to B-cell activation is the involvement of a specific protein kinase, known as Bruton's tyrosine kinase (Btk) in the activation cascade. The critical role of this kinase was revealed when its deficiency was found to be associated with infantile agammaglobulinemia (Bruton's disease). c. The subsequent sequence of events seems to have remarkable similarities with the activation cascade of T lymphocytes. Activation and translocation of common transcription factors (e.g., NF-AT, NF- κ B) induce overlapping, but distinct, genetic programs. For instance, in B cells, NF- κ B activates the expression of genes coding for immunoglobulin polypeptide chains. (NF- κ B received its designation when it was originally described as a transcription factor that binds to the enhancer region controlling the gene coding for kappa- type immunoglobulin light chains.) 4. Additional signals necessary for B-cell proliferation and differentiation depend both on soluble molecules (interleukins-2,4,5, and 6) and cell-cell contact (see below). Page 66 XI. Stimulation of a B-Lymphocyte Response by a T-Dependent Antigen The stimulation of a B-cell response with a T- dependent antigen involves several cell populations cooperating with each other in the activation, proliferation, and differentiation processes. T-cell help is mediated both by soluble factors (cytokines) and by interactions between complementary ligands (co-stimulatory molecules) expressed by T cells and B cells. A. The naive B cell is initially stimulated by recognition of an epitope of the immunogen through the membrane immunoglobulin. Two other sets of membrane molecules are involved in this initial activation, the CD45 molecule and the CD19/CD21/CD81 complex. Whether the activation of CD45 involves interaction with a specific ligand on the accessory cell remains to be determined. In the CD19/CD21/CD81 complex, the only protein with a known ligand is CD21, a receptor for C3d (a fragment of the complement component 3, C3). It is possible that B cells interacting with bacteria coated with C3 and C3 fragments may receive a co-stimulatory signal through the CD19/CD21/CD81 complex. B. In the same microenvironment where B lymphocytes are being activated, helper T lymphocytes are also activated. Two possible mechanisms could account for this simultaneous activation: 1. The same accessory cell (i.e., a macrophage) may present not only membrane-absorbed, unprocessed molecules with epitopes reflective of the native configuration of the immunogenic molecule to B lymphocytes, but also MHC-II-associated peptides derived from processed antigen to the helper T lymphocytes. 2. The activated B cell may internalize the immunoglobulin-antigen complex, process the antigen, and present MHC-II-associated peptides to the helper T cells. C. The proper progression of the immune response will require that accessory cells (macrophages or B cells), helper T lymphocytes, and B lymphocytes interact in a circuit of mutual activation (Figures 4.8 and 4.9): 1. The T lymphocyte receives the following activation signals from accessory cells. a. Recognition of the MHC-II-associated peptide by the TcR. b. Signals mediated by CD4-MHC-II interactions. c. Signals mediated by the cell-cell interactions, which are facilitated by the up-regulation of some of the interacting molecules after initial activation, including: i. CD2 (T cell): CD58 (APC). ii. LFA-1 (T cell): ICAM-1, ICAM-2, ICAM-3 (APC). iii. CD40L (T cell): CD40 (APC). iv. CD28 (T cells): CD80, CD86 (APC). d. Signals mediated by interleukins, particularly IL-1 and IL-12. 2. The activated helper T cell, in turn, delivers activating signals to APC and B cells (Figure 4.9). a. Signals mediated by interleukins and cytokines. i. IL-2 and IL-4 which stimulate B-cell proliferation and differentiation. ii. Interferon- γ , which stimulates APC, particularly macrophages. Page 67 Figure 4.8 A diagrammatic representation of the induction of a T-dependent response to a haptencarrier conjugate. In this diagram the professional APC (macrophage) is responsible for adsorbing and presenting the hapten-carrier conjugate to a B lymphocyte. The B lymphocyte depicted in the diagram recognizes the hapten, internalizes the hapten-carrier conjugate, processes the carrier, and presents a carrier-derived peptide to a helper T lymphocyte. This will result in the initial steps of cross-activation between T helper and B lymphocytes. Figure 4.9 Diagrammatic representation of the sequence of events leading to the stimulation of a T-dependent B-cell response. Page 68 b. Signals mediated by cell-cell interactions, involving CD40L (gp39, on T cells) and CD40 (on B cells). 3. At the same time, the helper T cells continue to proliferate and differentiate. a. The IL-2 receptor is up-regulated and increases its affinity for IL-2; consequently, IL-2 participates in autocrine and paracrine signaling, which results in T-lymphocyte proliferation. b. As a consequence of signaling through the CD40 molecule, B cells express CD80 and CD86, which deliver differentiation signals to T cells through the CD28 family of molecules. Additional activation signals are delivered as a consequence of interactions involving other sets of membrane molecules. D. In this type of response, a functional subpopulation of helper T lymphocytes specialized in assisting B-cell activation and differentiation emerges (TH2 lymphocytes). Another functional subpopulation, TH1 lymphocytes, assists the differentiation of cytotoxic T lymphocytes and NK cells as well as the activation of macrophages. Several factors appear to control the differentiation of TH2 cells as opposed to TH1 cells, including the affinity of the interaction of the TcR with the MHC-II-associated peptide, the concentration of MHC-associated peptide, cytokines, and signals dependent on cell-cell interactions (Table 4.1). The two subpopulations of helper T lymphocytes differ in the repertoire of cytokines they release (Table 4.2). E. Cell-cell contact phenomena play at least an equally significant role as lymphokines in promoting B-cell activation, either by delivering co-stimulatory signals to the B cell, or by allowing direct traffic of unknown factors from helper T lymphocytes to B lymphocytes. a. Transient conjugation between T and B lymphocytes seems to occur constantly, due to the expression of complementary CAM on their membranes (for example, T cells express CD2 and CD4, and B cells express the respective ligands, CD58 (LFA-3) and MHC-II; both T and B lymphocytes Table 4.1 Signals Involved in the Control of Differentiation of TH1 and TH2 Subpopulations of Helper T Lymphocytes Signals favoring TH1 differentiation Signals favoring TH2 differentiation Interleukin-12 Interleukin-4 a Interferon γ b Interleukin-1 Interferon- α Interleukin-10 CD28/CD80 interaction CD28/CD86 interaction High density of MHC-II—peptide complexes on the APC membrane Low density of MHC-II—peptide complexes on the APC membrane High-affinity interaction between TcR and the MHC-II/peptide complex Low-affinity interaction between TcR and the MHC- II/peptide complex a Released initially by undifferentiated TH cells (also known as TH0) after stimulation in the absence of significant IL-12 release from APC; IL-4 becomes involved in an autocrine regulatory circuit that results in differentiation of TH2 cells and in paracrine regulation of B-cell differentiation. b Interferon gamma does not act directly on TH1 cells, but enhances the release of IL-12 by APC, and as such has an indirect positive effect on TH1 differentiation. Page 69 Table 4.2 Interleukins and Cytokines Released by TH1 and TH2 Helper T Lymphocytes TH1 interleukins/cytokines Target cell/effect Interleukin-2 TH1 and TH2 cells/expansion; B cells/expansion, differentiation Interferon-γ Macrophages/activation; TH1 cells/differentiation; TH2 cells/downregulation TNF- β (lymphotoxin) TH1 cells/expansion; B cells/homing TH2 interleukins/cytokines Interleukin-4 TH2 cells/expansion; B cells/differentiation; APC/activation Interleukin-5 Eosinophils/growth and differentiation Interleukin-6 B cells/differentiation; plasma cells/proliferation; TH1, TH2 cells/activation; CD8+ T cells/differentiation, proliferation Interleukin-10 TH1, TH2 cells/down-regulation; B cells/differentiation Interleukin-13 Monocytes, macrophages/down-regulation; B cells/activation, differentiation TH1-TH2 interleukins/cytokines Interleukin-3 B cell/differentiation; macrophage/activation TNF- α B cell/activation, differentiation Granulocyte/monocyte CSF B cell/differentiation express ICAM-1 and LFA-1 and can engage in homotypic interactions through these molecules). b. When the B lymphocyte presents an antigen-derived peptide on its MHC-II, which is specifically recognized by the T lymphocyte, the two cells modulate the expression of membrane molecules and cell-cell conjugates becomes more stable. c. In stable conjugates of cooperating T and B cells, a reorganization of the cytoskeleton is seen on the T lymphocyte. The microtubule organizing center and the Golgi apparatus move to the pole of the T cell closer to the point of adhesion with the B cell. This reorganization implies unidirectional transport of proteins from the T lymphocyte to the B lymphocyte, and the membranes of the two interacting cells fuse for a brief period of time. Thus, it seems very likely that important signals are transmitted from cell to cell during conjugation. It is not known whether or not those signals are delivered in the form of interleukins or as of yet uncharacterized molecules. F. The continuing proliferation and differentiation of B cells into plasma cells is assisted by several soluble factors, including IL-4, released by TH2 cells, IL-6, and IL-14 (previously known as high molecular weight B-cell growth factor), released by T lymphocytes and accessory cells. G. At the end of an immune response, the total number of antigen-specific T-and B-lymphocyte clones will remain the same, but the number of cells in those clones will remain increased severalfold. The increased residual population of antigen-specific T cells is long-lived, and is believed to be responsible for the phenomenon known as immunological memory. [...]... and Variable Regions The light chains of human immunoglobulins are composed of 21 1 to 21 7 amino acids As mentioned above, there are two Table 5.3 IgA Subclasses IgA1 IgA2 Distribution Predominates in serum Predominates in secretions Proportions in serum 85% 15% Allotypes ? A2m(1) and A2m (2) H-s-s-L + - in A2m(1); + in A2m (2) Page 81 major antigenic types of light chains (κ and λ); when the amino acid... into antibody-secreting cells 4.3 Which of the following steps of the immune response is likely to be impaired by a deficiency of cytoplasmic transport-associated proteins (TAP-1, TAP -2 ) ? A Assembly of a functional B-cell receptor B Expression of the CD3-TcR complex C Formation of stable complexes of viral derived peptides with MHC-I proteins D Translocation of nuclear binding proteins from the cytoplasm... binding to the receptor Self-Evaluation Questions Choose the ONE best answer 5.1 Which of the following antibodies would be most useful to assay human secretory IgA in secretions? A Anti-IgA1 antibodies B Anti-IgA2 antiserum C Anti-J chain antibody D Anti-kappa light chains E Anti-secretory component 5 .2 Which of the following is a likely event resulting from the mixture of an F(ab' )2 fragment of a given... (D) Interleukin- 12 is released by accessory cells (particularly monocytes and macrophages) and is believed to be one of the primary determinants of the differentiation of TH1 lymphocytes Interleukin-4, released by activated T cells in the absence of a co-stimulatory signal from IL- 12, plays a similar role in the differentiation of the TH2 population 4 .2 (B) B lymphocytes express MHC-II molecules, and... relevance is related to allergic reactions 1 IgE has the unique property of binding to Fcε receptors on the membranes of mast cells and basophils The binding of IgE to those receptors has an extremely high affinity (7.7 × 109 1/M-1), about 100-fold greater than the affinity of IgG binding to monocyte receptors Page 87 2 The high affinity binding of IgE to basophil membrane receptors is the basis for... concentration (mg/dl) Intravascular distribution Page 80 Table 5 .2 IgG Subclasses IgG1 IgG2 IgG3 IgG4 60% 30% 7% 3% Half-life (days) 21 21 7 21 Complement fixationa ++ + +++ - Segmental flexibility +++ + ++++ ++ Affinity for monocyte and PMN receptors +++ + ++++ + Binding to protein Ab ++ ++ - ++ Binding to protein Gc +++ +++ +++ +++ % of total IgG in normal serum aBy the classical pathway bA protein... dimeric IgA to Poly-IgR seems to be the first step in the final assembly and transport process of secretory IgA Surface-bound IgA is internalized and Poly-IgR is covalently bound to the molecule, probably by means of a disulfide-interchanging enzyme that will break intrachain disulfide bonds in both IgA and Poly-IgR and promote their rearrangement to form interchain disulfide bonds joining Poly-IgR to an... individuals of a different genetic makeup 4.8 (B) 4.9 (B) IL-4 and IL-10 synthesis are characteristic of a TH2 response, associated with B-cell activation but with lack of differentiation of cytotoxic T cells and NK cells IL- 12 synthesis would induce a TH1 response, with overproduction of IL -2 and TNFα The infected animals are not likely to eliminate the infection, since antibodies are not effective... Exp Med., 1 82: 1591, 1995 Gold, M.R., and Matsuuchi, L Signal transduction by the antigen receptors of B and T lymphocytes Int Rev Cytol., 157:181, 1995 June, C.H., Bluestone, J.A., Nadler, L.M., and Thompson, C.B The B7 and CD28 receptor families Immunol Today, 15: 321 , 1994 Justement, L.B., Brown, V.K., and Lin, J Regulation of B-cell activation by CD45: a question of mechanism Immunol Today, 15:399,... types of chains will be combined into complete IgG molecules, without surpluses of any given chain The assembly of a complete IgG molecule can be achieved either by associating one H and one L chain to form an HL hemi-molecule, and joining in the next step two HL hemi-molecules to form the complete molecule (H2L2), or by forming H2 and L2 dimers that later associate to form the complete molecule D When . T-cell proliferation, such as those encoding interleukin -2 (IL -2 ) , the IL -2 receptor gene, and c-myc. d. The binding of IL -2 to its receptor triggers an additional activation pathway involving. helper T cells continue to proliferate and differentiate. a. The IL -2 receptor is up-regulated and increases its affinity for IL -2 ; consequently, IL -2 participates in autocrine and paracrine signaling,. such as CD2, CD28, CD40 ligand (CD40L, CD154, gp39), LFA-1 and ICAM-1. These molecules have counterparts on the APC: CD58 (LFA-3), CD80/86, CD40, ICAM-1, and LFA-1 (ICAM-1 and LFA-1 are expressed