MONITORING THE CELLULAR COMPONENTS OF THE IMMUNE SYSTEM DURING CLINICAL TRIALS: A TRANSLATIONAL MEDICINE APPROACH - Flow Cytometry in Drug Discovery and Development - page 188

9.2 BASIC RESEARCH: CELLULAR COMPONENTS
OF THE IMMUNE SYSTEM

The immune system has traditionally been subdivided into two distinct arms, the
innate immune system and the adaptive immune system. In recent years, the
interaction and interdependence between the two systems have come to light and
thus the distinctions between the two have been blurred. Themajor effector cells of the
innate immune system include neutrophils, monocytes, dendritic cells (DCs), and
natural killer (NK) cells. The innate immune system provides the first line of defense
against pathogens that are identified by pattern recognition-type cellular receptors
such as the Toll-like receptors (TLR). These evolutionarily conserved receptors have
limited diversity and require no antigenic priming. The innate immune cells bearing
these receptors have no capacity for memory responses. In contrast, in the adaptive
immune system foreign antigen is detected by highly specific, membrane-bound
receptors on the surface of T and B lymphocytes. The T-cell antigen receptor (TCR)
and the B-cell antigen receptor (BCR or membrane immunoglobulin) are highly
specific and have the capacity for unlimited diversity. Although the adaptive immune
system requires antigen priming, once activated it is capable of long-term immunity
by mounting vigorous memory responses even decades after the initial exposure.
Functional responses of the adaptive immune system are either cellular or humoral
(antibody-driven) responses. T-lymphocyte cells represent 50-90% of the peripheral
blood lymphocytes and are often referred to as “directors” of the adaptive immune
response. T-lymphocyte cells are divided into two major subsets: T-helper cells (Th)
expressing CD4 and cytotoxic T cells (CTLs) expressing CD8. The immunoglobulin
(Ig) producing B lymphocytes are the principal cellular mediators of humoral immune
responses. Most of the adult B cells (80%) are found in the lymph nodes and thus they
represent only 4-25% of the peripheral blood lymphocytes.
In the initial stages of an antigen-specific immune response, the interaction of
pathogens (intracellular, parasitic, and extracellular) or allergens with the cellular
components of the innate immune system results in cytokine production and antigen
presentation to the cellular components of the adaptive immune system (Figure 9.4).
Next na ve, or antigen-inexperienced, T-lymphocyte cells proliferate and generate a

variety of antigen-specific effector andmemory cells with distinct functions [9]. After
the immune response has subsided, central memory cells patrol lymphoid tissue while
effector memory cells actively launch immune responses to subsequent assaults. It is
not yet clear which cells are actually most important for maintaining immunological
memory. CD4 T-lymphocyte cells are the crucial component of the adaptive immune
system. Effector CD4 T-lymphocyte cells are heterogeneous in terms of their surface
phenotype, cytokine production, and homing potential; they differentiate into Th1,
Th2, Th17, and regulatory T cell (Treg) (Figure 9.5). Interferon gamma (IFN- g ) and
interleukin-12 (IL-12) initiate the differentiation of Th1 cells that are characterized by
IFN- g secretion and induction of inflammatory immune responses, and are required
for cell-mediated immunity against intracellular pathogens. In contrast, IL-4 drives
Th2 cell differentiation that results in IL-4 production, induction of humoral immune
responses, and clearance of extracellular pathogens. More recently, Th17, a distinct

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