The immune system: basis of so much health and disease: 4. immunocytes

T-Cells

T-lymphocytes are produced in the bone marrow from the pluripotential bone marrow haemopoietic stem cell and migrate to the thymus (hence the T) where they complete their development (Article 3). T-cells are particularly important in acquired immunity against:

T-cells are also involved in mediating immunological processes such as:

These functions are mediated by different subsets of T-lymphocytes distinguished by unique surface markers known as cluster of differentiation (CD); these surface markers also mediate antigen recognition, and interactions between T-cells and APCs by functioning as cell surface receptors (known as T-cell receptors, TCRs).

T-cells recognize antigens through their TCR. Some T-cells develop TCRs as they mature and these have an affinity to bind to MHC Class II antigens, and will become T-helper (Th) cells (identified by their expression of CD4 (CD4⁺ cells). Other T-cells as they mature develop TCRs that have an affinity to bind to major histocompatibility complex (MHC) Class I antigens and will become T-cytotoxic (Tc) cells identified by their expression of CD8 (CD8⁺ cells). Other groups of T-cells include gamma-delta T-cells (γδ T-cells) and regulatory T-cells (T-regs) (Table 1).

CD4⁺ cells

Features of CD4⁺ cells include the following:

Healthy adults usually have CD4 ⁺ T-cell counts of 1,000 or more per cubic millimeter (mm) of blood;

Also known as T-helper [Th] cells, CD4⁺ T-cells are important in the initiation of immune response by providing help to other cells, such as B-cells and macrophages;

Th-cells become activated when they are presented with antigens by MHC Class II molecules, which are expressed on the surface of APCs;

Activated Th CD4⁺ cells expand and differentiate into different effector T-helper (Th) subsets and secrete several cytokines and colony-stimulating factors (CSFs) that can:

Induce B-cell differentiation;

Induce CD8⁺ cytotoxic T-cell proliferation; and

Produce various soluble mediators (cytokines).

Th subsets include Th₁, Th₂ and Th₁₇ – characterized by distinct effector functions and cytokine production (Table 2);

Th₁-cells produce cytokines involved mainly in cell-mediated immune response and inflammation, eg IFN-γ, TNF-β, IL-2, IL-3 and IL-12;

Th₁-cells are important for maximizing the killing efficiency of macrophages in the elimination of intracellular pathogens. They also promote the proliferation of cytotoxic CD8⁺ T-cells involved in type IV immune responses;

Th₁-cells are suppressed by IL-10;

Th₂-cells secrete IL-4, IL-13, and IL-25 thus stimulating B-cells to produce antibodies of immunoglobulin classes IgG, IgA and IgE;

Th₂-cells are involved in type II and type III immune reactions, and in elimination of extracellular pathogens;

Th₂-cells are suppressed by interferon;

Th₁₇-cells produce IL-17 and IL-22 which stimulate epithelial cells to produce antimicrobial proteins active against Staphylococci and Candida.

Table 2. Th-cell subsets, functions, and cytokines they release.

	Th1	Th2	Th17
Main cytokines	IL-2	IL-4	IL-17
	IFN-gamma	IL-5	IL-22
	IL-12	IL-10
Main defensive function against	Intracellular microbes	Helminths and extracellular microbes	Extracellular microbes
Involvement with disease	Inflammatory and autoimmune disease	Allergies	Autoimmune and auto-inflammatory disease

Th₁₇-cells play an important role in defence against extracellular pathogens not efficiently cleared by other cells (Figure 1).

CD8⁺ cells

CD8⁺ cells (cytotoxic T-cells [Tc]), are important in:

Eliminating virally-infected cells;

Eliminating cancer cells, and

Mediating transplant rejection.

CD8⁺ cells constitute 35% of peripheral T-cells, and can recognize their targets by binding to antigens associated with MHC Class I molecules, which are expressed on the surface of almost all host cells. When exposed to infected/damaged cells, Tc-cells release their cytoplasmic storage granules that contain proteins, such as perforins, esterases (granzymes), and toxic cytokines which can induce apoptosis (programmed cell death) of the infected/damaged cells (Figure 2).

B-Cells

B-lymphocytes develop in the bone marrow from the pluripotential bone marrow haemopoietic stem cell, and migrate to secondary lymphoid organs (spleen and lymph nodes) where they complete their maturation. Once B-cell antigen receptors become functional, a transitional type 1 (T1) of B-cells migrate from the bone marrow to secondary lymphoid organs to mature further. Within the secondary lymphoid organs, T1 B-cells develop into transitional type 2 (T2)B-cells which finally develop into mature B-cells. B-cell development and maturation is characterized by rearrangement of the immunoglobulin (Ig) genes, and the expression on the cell surface of immunoglobulin receptors specific for a single antigenic epitope. B-cells can, via these receptors, recognize antigens directly (Figure 3).

Antibody responses

Antibody responses include:

B-cells typically require Th-cell help to generate an effective antibody response (termed T-dependent antigen processing). T-dependent antigens bind to the B-cell immunoglobulin receptor, are internalized, processed, and presented in association with MHC Class II molecules to T-cells. The complex of antigen/MHC Class II is recognized by an antigen-specific T-cell, which then becomes activated, secreting cytokines (lymphokines) that act on activated B-cells to promote proliferation and/or differentiation (Figure 4).

B-cells can react without Th-cell help to T-independent antigens, which include some polysaccharides, and polymeric, or degradation-resistant antigens, however, these antigens induce a weaker humoral immune response, only IgM is secreted, and memory B-cells are not formed (Figure 5).

The first contact with a specific antigen elicits a primary immune response in which B-cells undergo clonal selection, and differentiate into antibody-producing plasma cells, and memory cells.

The primary immune response is complex and not rapid – it can last from days to several weeks and initially consists of a peak of IgM antibodies followed later by a switch to IgG.

During the immune response, the antibody affinity increases (affinity maturation), dependent on somatic mutation in the combining site (the immunoglobulin V-region), and competitive selection of responding clones.

Memory B-cells (and memory T-cells) develop so that subsequent exposure to the same antigen elicits a secondary immune response.

The secondary immune response develops more rapidly than a primary response, with mainly IgG antibodies, reaching a greater magnitude and lasting longer than the primary immune response.

B-cells that do not encounter the antigen, for which they are specific, die within a few days.

Humoral immunity (antibodies) protects via the following:

Neutralizing bacterial toxins (eg antitoxins to diphtheria or tetanus);

Attaching to bacterial surfaces and preventing adherence to their target cells;

Activating complement, leading to bacteriolysis (and inflammation);

Acting as opsonins which coat microbes, enhancing their phagocytosis;

Clumping pathogens (agglutination) leading to phagocytosis.

Humoral (antibodies) immunity can be either passively acquired or actively acquired.

Passively acquired immunity can be:

Natural (antibodies pass through placenta to foetus); or

Artificial (injection of antibodies, such as gamma globulin).

Actively acquired immunity can be:

Natural (follows clinical or sub-clinical infection); or

Artificial (follows immunization [vaccination] with live or killed infectious agents or their products).