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by contrast, bind specific soluble molecules (insect toxins, venom, and allergens) via immunoglobulin.

This is endocytosed, processed, and presented on surface MHC II.39,63–65

Lymphocytes

B, T, and NK cells comprise this lineage of inflammatory cells (Table 7-1). B and T cells are central to

the adaptive immune response, whereas NK cells lack antigen specificity and primarily function during

innate immune response. NK cells are the first line of defense against many viral infections. The loss of

surface expression of MHC class I molecules as occurs with virus-infected cells serves as a target for NK

cells.39,66 Alternatively, NK cells bind cell-bound antibody and participate in antibody-dependent cell

cytotoxicity. Cells targeted by either mechanism are induced to undergo cell death.

B Lymphocytes

B cells, though of bone marrow origin, attain full maturation within extramedullary sites such as lymph

nodes, the spleen, and the mucosal lymph nodules of tonsils and Peyer patches. With activation, B cells

differentiate into antibody-producing plasma cells, which through the elaboration of antibody, aid the

neutralization of viruses and bacterial toxins, and facilitate opsonization for phagocytosis and

complement activation.4 Activation requires antigen binding to cell surface receptors and stimulation by

TH cell–derived cytokines; they do not need the assistance of APCs. Polyclonal B-cell activation can

occur in a T-cell–independent mechanism if the antigen has a large repeating polymeric sequence.39,67

T Lymphocytes

Development of T lymphocytes begins within the marrow and is completed in the thymus. The final

population profile is determined by apoptotic processes of both positive and negative selection.68 Any

protein or antigen of host origin is presented by APCs, and thymocytes reactive to these self-proteins are

deleted.69 Alternatively, expansion of cell lines recognizing foreign, or rather nonself antigen, occurs

through positive selection. IL-7 provides the stimulation for proliferation and differentiation of

developing T cells. Ultimately, two lines of mature cells, CD4+ and CD8+, will develop.69

Lymphocytes, the smallest of the leukocytes, constitute approximately 20% of circulating leukocytes.4

Most circulating lymphocytes are T cells, and 60% of those are CD4+, a marker of a TH phenotype. The

other 40% are CD8+, called cytotoxic T cells, TC. The normal ratio of CD4+/CD8+ is 2:1.4 Lymphocytes

continuously recirculate through lymph nodes, spleen, lymphatics, lymph nodules, and blood, providing

continuous surveillance. Encounter with a particular antigen initiates activation toward an effector T

cell. Activation of a T cell requires bind to its specific antigen plus a costimulatory signal provided by

the interaction between costimulatory molecules on the APC and their cognate receptors on the T cell.39

Naïve T cells circulate continuously between blood and lymphoid organs, making contact with many

APCs and the epitopes of the antigens they express.70 Initially, lymphocytes enter the cortical region of

lymph nodes by migrating across the high endothelial venules, a process mediated by the selectin family

of receptors. L-selectin, which is found constitutively on all lymphocytes, binds sialyl Lewis

carbohydrate on the endothelium.39 For example, L-selectin on lymphocytes binds GlyCAM-1 on the

high endothelial venules in lymph nodes. In mucosal tissues, L-selectin and endothelial MAdCAM-1

guide emigration. Migration across the endothelium requires integrins, in particular LFA-1 and its

interaction with ICAM-1 and ICAM-2 on endothelial cells.71 Most lymphocytes are carried back to the

blood by the efferent lymphatics. If a T lymphocyte recognizes its specific antigen on the surface of an

APC, it remains for several days, then returns to the blood as an armed effector T cell.39

Adhesion molecules mediate many of the transient interactions between T cells and APCs that are

required for the T cell to sample each antigen it encounters. Lymphocyte LFA-1 can bind the APC in a

loose, reversible fashion by any of the ICAM molecules on APCs. If a match between T cell and antigen

is found, conformational changes in LFA-1 greatly increase its affinity for ICAM-1 and ICAM-2 to

stabilize the interaction. The T cell can then proliferate and differentiate into an effector cell. Effector T

cells lose surface expression of L-selectin and no longer circulate through lymphoid tissue. Instead they

express VLA-4, an integrin, which binds vascular endothelium at sites of infection, and the cell is

retained at the focus. Effector T cells have increased LFA-1 and CD2 adhesion molecule expression that

facilitate tight binding to target cell.72,73

Antigen binding in the appropriate context provides the signal for clonal expansion and differentiation

of T cells into effector and memory lymphocytes. The appropriate contact is composed of antigen

complexed with MHC class II molecules on APCs, costimulators, and cytokines produced by the APCs

and by the T cells themselves. This first encounter of naïve T cells with antigen is the primary immune

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response, which serves to induce the formation of effector and memory T cells. These activated T cells

hone to peripheral tissues where, upon reexposure to their specific antigen, they activate macrophages

to eliminate phagocytosed microbes and induce B-cell differentiation and antigen-specific antibody

secretion. The CD8+ CTLs kill infected host cells and tumor cells that display class I MHC-associated

antigen. Naïve T cells require activation by DCs, whereas effector T cells can respond to antigens

presented by a wider variety of APCs, such as macrophages and B lymphocytes. Not surprisingly,

differentiated effector and memory T cells possess lower thresholds for costimulation and require lower

antigen concentration for activation than naïve T cells.

In general, antigen presented on MHC II molecules is the prototypical stimulus for CD4+ T-cell

activation and the subsequent production of a variety of cytokine mediators, including IL-2, which

stimulate further expansion and activation. However, the circumstances under which this activation

occurs may dictate disparate paths of differentiation, producing T-cell subsets with distinct cytokine

profiles and effector functions. These differing phenotypes have been utilized to characterize two

distinct subsets: TH1 and TH2.59,60,74 IL-12 derived from phagocytes infected with intracellular pathogen

provides the necessary signal for TH1 differentiation.39 IL-12 also stimulates production of IFNγ, the

principle macrophage activator, by NK cells and CD4+ lymphocytes. Interferons stimulate TH1

development by augmenting phagocytic IL-12 production and by maintaining IL-12 receptor expression

on CD4+ T cells. The principal effector action of TH1 cells is the activation of macrophages through the

production of IFNγ, GM-CSF, TNFα, CD40L, and FasL.39,59,60,74 They regulate production of opsonizing

and complement fixing antibodies and are effectors of phagocyte-dependent responses. This

inflammatory response, also referred to as cell-mediated immunity or delayed-type hypersensitivity,

provides one major arm of the adaptive immune response; it is mediated by CD4+ and CD8+

lymphocytes and macrophages.

The principal stimulus for TH2 differentiation is IL-4, which is derived from T cells, mast cells, and

basophils.59,60,74 These cells are the cellular effectors of humoral immunity and provide the other major

arm of the adaptive immune response, which is mediated by TH2 CD4+ cells, B cells, plasma cells, and

antibodies. They produce IL-4, IL-5 and CD40L, thereby inducing B-cell activation and antibody

production, and a host of other proinflammatory and anti-inflammatory cytokines.39 Activation of mast

cells and eosinophils by extracellular pathogens is associated with activation of TH2 cells. TH2 cells quell

the inflammatory response by inhibiting macrophage functions and TH1 responses. They are considered

the anti-inflammatory arm of cell-mediated inflammation. Helper T cells that express both TH1 and TH2

patterns of cytokine expression have been called TH0 cells, and further studies will certainly discern

other subsets of T cells.4,74

T-cell activation, differentiation, and expansion are orchestrated by the T cell itself. The responding T

cell, in an autocrine fashion, serves as both source and target of a variety of mediators stimulating

growth. The principal autocrine growth factor is IL-2, which is induced by signaling regulated by the

phosphatase calcineurin (see below).75 IL-15 stimulates the proliferation of CD8+ T cells, especially

memory cells of the CD8+ subset. After antigen exposure, the numbers of T cells specific for that

antigen may increase to about 1 in 10 for CD8+ and 1 in 1000 to 10000 for CD4+ cells.4

After activation, some proliferating T cells will differentiate into effector cells that eliminate antigens

and activate other immune cells. Mature CD4+ cells induce the activation of mononuclear phagocytes

and B cells. CD8+ cells differentiate into CTL that recognize viral and other intracellular pathogen

antigens that are presented in the context of MHC class I molecules and induce target cell death by

releasing the cytotoxins perforin and granzymes from cytoplasmic granules. Granzymes are serine

proteases that trigger DNA fragmentation and apoptosis. Perforin stimulates cell membrane pore

formation that facilitates granzyme entrance into cells. Apoptosis can also be induced by the binding of

Fas ligand on CTL to Fas on the target cell. CTLs also release the cytokines IFNγ, TNFα, and CC

chemokines. IFNγ and certain CC chemokines have antiviral properties, and both are potent activators

of macrophage function. IL-2 produced by CTL and local helper CD4+ lymphocytes expands the CTL,

and IL-12 released by APC stimulates CTL activity. As with CD4+ cells, early evidence suggests that the

population CD8+ may be divided into TC1 and TC2 cells based on their cytokine profiles and effector

functions.39,58–60

Other T cells will mature into long-lived functionally quiescent memory cells. Upon antigen

reexposure, a cell surface rich in adhesion molecules (i.e., integrins, CD44) facilitates rapid and efficient

migration to peripheral sites of infection.4 These cells accumulate over time and in the adult human

comprise more than half of the circulating T cells.

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