Immune responses are mediated by specific cells with defined functions. Characteristics of these cells, their appearances, and numbers are presented in Fig. 1 and in Tables 1 and 2. For each of the cells know CARP: cell-surface markers (e.g., CD4, TCR, etc.), actions (kill, suppress, activate, etc.), role (type of response), and products (cytokines, antibody, etc.). The white blood cells can be distinguished on the basis of (1) morphology, (2) histologic staining, (3) immunologic functions, and (4) intracellular and cell-surface markers.
Fig1. Morphology and lineage of cells involved in the immune response. Pluripotent stem cells and colony-forming units (CFUs) are long-lived cells capable of replenishing the more differentiated functional and terminally differentiated cells. (Modified from Abbas, A.K., Lichtman, A.H., Pillai, S., et al., 2015. Cellular and Molecular Immunology, eighth ed. Elsevier, Philadelphia, PA.)
Table1. Cells of the Immune Response
Table2. Normal Blood Cell Counts
B and T lymphocytes can be distinguished by expression of antigen receptors on their surfaces, immunoglobulin (B-cell receptor (BCR)) for B cells, and T-cell receptors (TCRs) for T cells. Other cell-surface proteins distinguish subsets of these and other types of cells. These marker proteins are identified with monoclonal antibodies. They are defined within clusters of differentiation (as determined by all of the monoclonal antibodies that recognize the same molecule [e.g., CD4] or group of molecules [e.g., CD3]) as indicated by “CD” (cluster of differentiation) numbers (Table 3). In addition, all nucleated cells express class I major histocompatibility complex (MHC I) antigens (human: HLA-A, HLA-B, HLA-C).
Table3. Selected Cluster Differentiation Markers of Importance
A special class of cells that are antigen-presenting cells (APCs) express class II MHC (MHC II) antigens (HLA-DR, HLA-DP, HLA-DQ). Cells that present antigenic peptides to T cells include dendritic cells (DCs), macrophage family cells, B lymphocytes, and a limited number of other cell types.
HEMATOPOIETIC CELL DIFFERENTIATION
The differentiation of white blood cells from their common progenitor cell, termed the pluripotent stem cell, yields the two main lineages of cells, myeloid and lymphoid cells. Differentiation of these cells begins during development of the fetus and continues throughout life. The pluripotent stem cell differentiates into different stem cells (sometimes referred to as colony-forming units) for the lymphoid (T, B, and innate lymphoid cells) or myeloid lineages. Within the myeloid lineage are the granulocytic, monocyte-dendritic cell, erythrocytic, and megakaryoblastic (source of platelets) lineages (see Fig. 1). The stem cells reside primarily in the bone mar row but can be isolated from the fetal blood in umbilical cords and as rare cells in adult blood. Differentiation of stem cells into the functional blood cells is triggered by specific cell-surface interactions with the stromal cells of the marrow and specific cytokines produced by these and other cells.
The bone marrow and thymus are considered primary lymphoid organs (Fig. 2). These sites of initial lymphocyte differentiation are essential to the development of the immune system. The thymus is essential at birth for T-cell development but shrinks with aging. Secondary lymphoid organs include the lymph nodes, spleen, skin, and mucosa-associated lymphoid tissue (MALT); the latter also includes gut-associated lymphoid tissue (GALT) (e.g., Peyer patches) and bronchus-associated lymphoid tissue (BALT) (e.g., lung). These sites are where DCs, innate lymphoid cells (ILCs), B and T lymphocytes, and other cells reside and respond to antigenic challenges. The primary and secondary lymphoid organs produce chemokines and express cell-surface adhesion molecules (addressins) that interact with homing receptors (cell adhesion molecules) to attract and retain these cells.
Fig2. Organs of the immune system. Thymus and bone marrow are primary lymphoid organs. They are sites of maturation for T and B cells, respectively. Cellular and humoral immune responses develop in the secondary (peripheral) lymphoid organs and tissues; effector and memory cells are generated in these organs. The spleen responds predominantly to blood-borne antigens. Lymph nodes mount immune responses to antigens in intercellular fluid and in the lymph. Tonsils, Peyer patches, and other mucosa-associated lymphoid tissues (blue boxes) respond to antigens that have penetrated the surface of mucosal barriers. (From Male, D., Brostoff, J., Roth, D.B., et al., 2013. Immunology, eighth ed. Elsevier, Philadelphia, PA.)
The spleen and lymph nodes are encapsulated organs with designated areas for B and T cells. These locations facilitate interactions that promote immune responses to antigen (Fig. 3). Proliferation of the lymphocytes and structural stromal cells in response to infectious challenge causes these tissues to swell (i.e., “swollen glands”).
Fig3. Organization of the lymph node. Beneath the collagenous capsule is the subcapsular sinus, which is lined with phagocytic cells. Dendritic cells, lymphocytes, and antigens are pumped into the lymph node from the afferent lymphatic system. The cortex contains B cells grouped in primary follicles with stimulated B cells in secondary follicles (germinal centers). The paracortex contains mainly T cells and dendritic cells (antigen-presenting cells). Each lymph node has its own arterial and venous supplies. Lymphocytes enter the node from the circulation through the specialized high endothelial venules in the paracortex. The inner region, termed the medulla, contains lymph- filled sinuses, both T and B cells and most of the lymph node plasma cells organized into cords of lymphoid tissue. Lymphocytes can leave the node only through the efferent lymphatic vessel. (Modified from Abbas, A.K., Lichtman, A.H., Pillai, S., et al., 2022. Cellular and Molecular Immunology, tenth ed. Elsevier, Philadelphia, PA.)
The lymph nodes are kidney-shaped organs, 2 to 10 mm in diameter, that filter the fluid that passes from intercellular spaces into the lymphatic system, almost like a sewage processing plant. The lymph node is constructed to optimize the meeting of the innate (DCs and macrophages) and the antigen-specific (B and T) cells to initiate and expand specific immune responses. Activated dendritic cells also use the lymphatics to travel to the lymph node. A lymph node consists of three layers:
1. The cortex: The outer layer contains mainly B cells, some T cells, follicular DCs, and macrophages arranged in structures called follicles. Upon stimulation for antibody production, germinal centers develop containing B cells and T follicular helper cells (Tfh) in a stromal cell matrix.
2. The paracortex: Contains T cells and DCs and the DCs present antigens to the T cells to initiate new T-cell responses.
3. The medulla: Contains B and T cells and antibody- producing plasma cells, as well as channels for the lymph fluid.
The spleen is a large organ that acts like a lymph node and also filters antigens, encapsulated bacteria, and viruses from blood and removes aged blood cells and platelets (Fig.4). The spleen consists of two types of tissue, the white pulp and the red pulp. The white pulp consists of arterioles sur rounded by lymphoid cells (periarteriolar lymphoid sheath) in which the T cells dominate and surround the central arteriole. The red pulp is a storage site for blood cells and the site of turnover of aged platelets and erythrocytes.
Fig4. Organization of lymphoid tissue in the spleen. The white pulp contains germinal centers and is surrounded by the marginal zone, which contains numerous macrophages, antigen-presenting cells, slowly recirculating B cells, and natural killer cells. The T cells reside in the periarteriolar lymphoid sheath (PALS). The red pulp contains venous sinuses separated by splenic cords. Blood enters the tis sues via the trabecular arteries, which give rise to the many branched central arteries. Some arteries end in the white pulp, supplying the germinal centers and mantle zones, but most empty into or near the marginal zones. (Modified from Abbas, A.K., Lichtman, A.H., Pillai, S., et al., 2022. Cellular and Molecular Immunology, tenth ed. Elsevier, Philadelphia, PA.)
The epidermis of skin contains keratinocytes, Langerhans cells and memory T cells, and the dermis contains DCs, B and T lymphocytes, macrophages, and mast cells. Large numbers of memory T cells continuously circulate into these layers of the skin. Keratinocytes in the epi dermis are part of the innate antimicrobial defense system.
MALT contains less structured aggregates of lymphoid cells (Fig. 5). For example, the Peyer patches along the intestinal wall have special cells in the epithelium (M cells) with channels that allow large antigens to move from the lumen into this mini lymph node-like structure to elicit responses. The immune cells are within defined regions (T [interfollicular] and B [germinal]). DCs, T cells, and B cells also reside in the lamina propria layer just under the epithelium. Once thought to be expendable, the tonsils are an important part of the MALT. These lymphoepithelial organs sample the microbes in the oral and nasal area. The tonsils contain a large number of mature and memory B cells (50%–90% of the lymphocytes) that use their antibodies to sense specific pathogens and, with DCs and T cells, can initiate immune responses. Swelling of the tonsils may be caused by infection or a response to infection. Similarly, the appendix is also important as a reservoir for normal flora bacteria and for facilitating interactions with immune cells.
Fig5. Lymphoid cells within the mucosa-associated lymphoid tissue (MALT) that are stimulated with antigen in Peyer patches (or lungs or another mucosal site) migrate via the regional lymph nodes and thoracic duct into the bloodstream and then to the lamina propria of the gut and probably other mucosal surfaces. Thus lymphocytes stimulated at one mucosal surface may become distributed throughout the MALT system. IgA, Immunoglobulin A. (Modified from Abbas, A.K., Lichtman, A.H., Pillai, S., et al., 2022. Cellular and Molecular Immunology, tenth ed. Elsevier, Philadelphia, PA.)
