Primary Immune Response

Signal 2 Signal 1

Genes Multiple Sclerosis

IL-2-gene

Cell nucleus

Phosphatases / kinases-^-

^J Cytoplasm

IL-2-gene

Cell nucleus

Fig. 2.11 Regulation of T-cell activation is controlled by multiple signals, including costimulatory signals (Signal 2). Stimulation of the T cell via the T-cell receptor (TCR; Signal 1) activates a tyrosine kinase, which in turn activates phospholipase C (PLC). PLC splits phosphatidylinositol bisphosphate (PIP2) into inositol trispho-sphate (IP3) and diacyl glycerol (DAG). IP3 releases Ca2+ from intracellular depots, whilst DAG activates protein kinase C (PKC). Together, Ca2+ and PKC induce and activate the phosphoproteins required for IL-2 gene transcription within the cell nucleus. Stimulation of a T cell via the TCR alone results in production of only very small amounts of IL-2. Increased IL-2 production often requires additional signals (costimulation, e.g., via CD28). Costimulation via CD28 activates tyrosine kinases, which both sustain the transcription process and ensure post-transcriptional stabilization of IL-2 mRNA. Immunosuppressive substances (in red letters) include cytostatic drugs, anti-TCR, anti-CD3, anti-CD28 (CTLA4), anti-CD40, cyclosporine A and FK506 (which interferes with immunophilin-calcineurin binding, thus reducing IL-2 production), and rapamycin (which binds to, and blocks, immunophilin and hardly reduces IL-2 at all). Anti-interleukins (especially anti-IL-2, or a combination of anti-IL-2 receptor and anti-IL-15) block T-cell proliferation.

for T cell activation to occur, antigen-transporting APCs must first reach the organized secondary lymphoid organs (Fig. 2.12), since proper contact between lymphocytes and APCs can only take place within these highly organized and

— Structure of Lymph Nodes and Germinal Centers

Skin Antigen ,— Langerhans cell

Primary B-cell blasts

— Structure of Lymph Nodes and Germinal Centers

Skin Antigen ,— Langerhans cell

Primary B-cell blasts

Paracortex Lymph Node

Efferent lymph vessel

HEV Paracortex (T region)

(high endothelial venules)

Secondary B-cell blasts

Efferent lymph vessel

HEV Paracortex (T region)

(high endothelial venules)

Secondary B-cell blasts

Plasma cell precursors and memory B cells

Fig. 2.12 Antigen carried by antigen-presenting cells (e.g., Langerhans cells in the skin which have taken up local antigens), or soluble antigens enter the marginal sinus of the lymph node through afferent lymphatic vessels. In the spleen, blood-borne antigens are taken up by specialized macrophages present in the marginal zone (marginal zone macrophages, MZM). Each lymph node has its own arterial and venous vascularization. Tand B cells migrate from blood vessels, through specialized venules with a high endothelium (HEV: high endothelial venules), into the paracortex which is largely comprised ofTcells. Clusters of B cells (so-called primary follicles) are located in the cortex, where following antigen-stimulation, secondary follicles with germinal centers develop (right side). Active B-cell proliferation occurs at this site. Differentiation of B cells begins with the proliferation of the primary B-cell blasts within the dark zone and involves intensive interaction with antigen-presenting dendritic cells (DC). Antibody class switching and somatic mutation follows and takes place in the light zone, where FDC (follicular dendritic cells) stimulate B cells and store the antigen-antibody complexes that function to preserve antibody memory. Secondary B-cell blasts develop into either plasma cells or memory B cells. Lymphocytes can only leave the lymph nodes through efferent lymph vessels.

Kayser, Medical Microbiology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

compartmentalized organs. The cytokines IFNy, IL-1, IL-2, IL-4, and IL-12 play an important role in this process—as do various other factors.

During the second phase (Fig. 2.13), activated T helper cells recognize the same MHC class II peptide complex, but on the surface of a B cell. Prior to this event, the B cell must have responded to the same antigen (by virtue of its Ig surface receptor recognizing a conformational antigenic epitope), then internalized the antigen, processed it, and finally presented parts of it in the form of linear peptides bound to MHC class II molecules on the cell surface for recognition by the T helper cell. The resulting B-T cell contact results in further interactions mediated by CD4, CD40, and CD28 (see Fig. 2.9, p. 65)—and sends a signal to the B cell which initiates the switch from IgM to IgG or other Ig classes. It also allows induction of a process of somatic mutation, and probably enhances the survival of the B cell in the form of a memory B cell.

Subpopulations of T Helper Cells

Soluble signaling substances, cytokines (interleukins), released from T helper cells can also provide an inductive stimulus for B cells. Two subpopulations of T helper cells can be differentiated based on the patterns of cytokines produced (Fig. 2.14). Infections in general, but especially those by intracellular parasites, induce cytokine production by natural killer (NK) cells in addition to a strong T helper 1 (TH1) response. The response by these cells is characterized by early gamma interferon (IFNy) production, increased levels of phagocyte activity, elimination of the antigen by IFNy-activated macrophages, production of IgG2a and other complement-binding (opsonizing) antibodies (see the complement system, pp. 86ff.), and induction of cytotoxic T-cell responses. IL-12 functions as the most important promoter of TH1 cell function and additionally acts as an inhibitor of TH2 cells.

In contrast, worm infections or other parasitic diseases induce the early production of IL-4, and result in the development of a TH2 response. TH2 cells, in turn, recruit eosinophils and induce production of IgGl and igE antibodies. Persons suffering from allergies and atopic conditions show a pathologically excessive TH2 response potential. IL-4 not only promotes the TH2 response but also inhibits TH1 cells.

Cytotoxic T Cells (CD8+ T Cells)

Mature CD8+ T cells perform the biologically important function of lysing target cells. Target cell recognition involves the association of MHC class I structures with peptides normally derived from endogenous sources, i.e., originating in the cells themselves or synthesized within them by intracellular parasites. Induction of cytotoxic CD8+Tcell response often does not require helper

Kayser, Medical Microbiology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

— Lymphocytes and APCs in the Primary Immune Response

— Lymphocytes and APCs in the Primary Immune Response

Primary Immune Response

cells—or only requires these cells indirectly. However, should the antigen stimulus and the accompanying inflammation be of a low-level nature, the quantity of cytokines secreted by the cytotoxic Tcells themselves may not suffice, in which case the induction of a CD8+ T cell response will be reduced unless additional cytokines are provided by helper T cells. The cytotoxic activity of CD8+ T cells is mediated via contact and perforin release (perforin renders the membrane of the target cell permeable resulting in cellular death). CD8+ T cells also function in interleukin release (mainly of IFNy) by which they mediate non-cytotoxic effector functions (Fig. 2.15). The role of perforin in contact-dependent direct cytolysis by natural killer (NK) cells and cytotoxic T cells (see also Fig. 2.17, p. 88) has been investigated in gene knockout mice. In these animals the perforin gene has been switched off by means of homologous recombination, and as a result they can no longer produce perforin. Per-forin-dependent cytolysis is important for the control ofnoncytopathic viruses, tumors, and transformed cells, but also plays a large role in the control of highly virulent viruses that produce syncytia (e.g., the smallpox virus). Release of noncytolytic effector molecules by CD8+ cells, mostly IFNy, plays a major role in control of cytopathic viruses and intracellular bacteria. Cytolytic effector mechanisms may also contribute to release of intracellular micro-organisms and parasites (e.g., tuberculosis) from cells that only express MHC class I.

3 Fig. 2.13 For the sake of simplicity, the principles illustrated here are based on an antigen (1) which only contains a single B epitope and a single T epitope. As an example, the structural B epitope (blue) is presenton the surface of the antigen; whilst the linear T epitope (red) is hidden inside it. An antigen-presenting cell (APC), or macrophage, takes up the antigen and breaks it down in a nonspecific manner. The T-cell epitope is thus released and loaded onto MHC class II molecules which are presented on the cell surface (2). AT helper cell specifically recognizes the Tepitope presented by the MHC class II molecule. This recognition process activates the APC (3a) (or the macrophages). T cells, APC, and macrophages all produce cytokines (Fig. 2.14), which then act on T cells, B cells, and APCs (causing up-regulation of CD40, B7)(3). This in turn stimulates the T cells to proliferate, and encourages the secretion of additional signaling substances (IL-2, IFNy, IL-4, etc.). A B cell whose surface Ig has recognized and bound a B epitope present on the intact antigen, will present the antigenic Tcell epitope complexed to MHC class II on its cell surface, in a manner similar to that described for the APC (4). This enables direct interaction between the T helper cell and the specific B cell, resulting in induction of proliferation, differentiation, and B-cell class switching from IgM to other Ig classes. The B cell finally develops into an antibody-producing plasma cell. The antibody-binding site of the produced antibody thus fits the B epitope on the intact antigen. The induction of cytotoxic effector cells by peptides presented on MHC class I molecules (violet) is indicated in the lower part of the diagram (5). The cytotoxic Tcell precursors do not usually receive contact-mediated T help, but are rather supported by secreted cytokines (mainly IL-2) (6). (Again, in the interest of simplicity, the CD3 and CD4 complexes and cytokines are not shown in detail; see Fig. 2.8, p. 61 for more on antigen presentation.)

Cytokines (Interleukins) and Adhesion

Cytokines are bioactive hormones, normally glycoproteins, which exercise a wide variety of biological effects on those cells which express the appropriate receptors (Table 2.6). Cytokines are designated by their cellular origin such that monokines include those interleukins produced by macrophages/ monocytes, whilst lymphokines include those interleukins produced by lymphocytes. The term interleukins is used for cytokines which mostly influence cellular interactions. All cytokines are cyto-regulatory proteins with molecular weights under 60 kDa (in most cases under 25 kDa). They are produced locally, have very short half-lives (a matter of seconds to minutes), and are effective at picomolar concentrations. The effects of cytokines may be paracrine (acting on cells near the production locus), or autocrine (the same cell both produces, and reacts to, the cytokine). By way of interaction with highly specific cell surface receptors, cytokines can induce cell-specific or more general effects (including mediator release, expression of differen

CD4+ T Helper Cell Subpopulations — and APCs during Immune Responses

Viruses Bacteria

Delayed type hypersensitivity (DTH)

Defenses against intracellular microorganisms

Viruses Bacteria

Delayed Type Hypersensitivity Th1

Delayed type hypersensitivity (DTH)

Defenses against intracellular microorganisms

IgGz

Fig. 2.14 TH1 and TH2 cells are derived from a TH0 cell, and undergo differentiation in the presence of help derived from cytokines, DC, macrophages, and other cell types. TH1 cells are activated byIL-12and IFNy and inhibited byIL-4; whilst for TH2 cells the reverse is true. Viruses and bacteria (particularly intracellular bacteria) can induce a TH1 response by activating natural killer cells. In contrast, allergens and parasites induce a TH2 response via the release of IL-4. However, the strong in-vitro differentiation of CD4+ Tcells intoTH1-TH2 subsets is likely to be less sharply defined in vivo.

IgGz

Fig. 2.14 TH1 and TH2 cells are derived from a TH0 cell, and undergo differentiation in the presence of help derived from cytokines, DC, macrophages, and other cell types. TH1 cells are activated byIL-12and IFNy and inhibited byIL-4; whilst for TH2 cells the reverse is true. Viruses and bacteria (particularly intracellular bacteria) can induce a TH1 response by activating natural killer cells. In contrast, allergens and parasites induce a TH2 response via the release of IL-4. However, the strong in-vitro differentiation of CD4+ Tcells intoTH1-TH2 subsets is likely to be less sharply defined in vivo.

tiation molecules and regulation of cell surface molecule expression). The functions of cytokines are usually pleiotropic, in that they display a number of effects of the same, or of a different, nature on one or more cell types. Below is a summary of cytokine functions:

■ Promotion of inflammation: IL-1, IL-6, TNFa, chemokines (e.g., IL-8).

■ Promotion of hematopoiesis: GM-CSF, IL-3, G-CSF, M-CSF, IL-5, IL-7.

■ Activating T cells: IL-2, IL-4, IL-10, IL-13, IL-15.

Immune Responses and Effector Mechanisms 79 Antiviral Protection by T Cells -

Noncytopathic virus \

Noncytopathic virus \

Immune Csf Positive Feedback Loop

Perforin JJT

Primary Immune Response

Perforin * mouse:

uncontrolled viral proliferation

Perforin JJT

Perforin * mouse:

uncontrolled viral proliferation

Control mouse: perforin lyses infected cells

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Responses

Post a comment