Cellular Immunity in Vertebrates

Vertebrates have a complex body plan. The subphylum Vertebrata is monophyletic. In other words, all vertebrates are descended from a common ancestor. They have a common body plan. The tissues and organs within vertebrate bodies are irrigated with a rich supply of blood vessels. At the centre of this vascular system is a muscular pump, the heart. Contractions of the heart muscle propels blood to distant parts of the body. This means that in vertebrates, the flow of blood occurs in a pressurised environment. It also means that the blood is a good medium for the transportation of cells and other molecules to most parts of the body.

In all vertebrates, blood itself is composed of a watery fluid with numerous cells suspended in it. The blood cells perform a variety of functions, including the transport of dissolved gases (erythrocytes) and host defence. Within the circulatory system, cells are rapidly transported to all parts of the body. Blood pressure is loosely correlated with body size, which means that even in the largest animals, most parts of their bodies will be supplied with blood. From an immunological perspective, this implies that most tissues within the vertebrate body will be under surveillance and protected against infections by the immune system.

When vertebrate blood is examined under the microscope, a variety of cell types (morphologies) are apparent. There are heavily pigmented cells, granulated cells, cells with fixed shapes and cells which are able to change their shapes. It is like a mini-United Nations of cells! The one thing that is common to all these cells is that they are unicellular. There is one other incredible thing about these diverse cells - they're all descended from the same ancestral cell type! We will explore this in the next section.

Lineages of blood cell types in mammals. Image from http://www.bpac.org.nz/resources/campaign/cbc/images/fig1.gif

The term 'haem' refers to a group of complex organic molecules which are based on a heterocyclic hydrocarbon ring known as porphyrin. Haem is the main pigment in vertebrate and is complexed to a protein called globin to produce the familiar blood pigment, haemoglobin. Haemoglobin is the major pigment in red blood cells (erythrocytes). In deference to this, the development of blood cells (all blood cells, not just the erythrocytes) is referred to as haematopoiesis.

It all starts with a particular type of precursor cells known as the haematopoietic stem cells (HSCs). These cells are pluripotent, which means that they can develop into virtually all types of blood cells. At acertainpoint in early development, the HSCs migrate to the bone marrow. The HSCs are now exposed to new environmental conditions (that is, the microenvironments of the bone marrow). The signals within the bone marrow trigger the HSCs to divide. After division, a proportion of the HSCs will remain as HSCs (i.e., replenish the stem cell population), while the remaining cells undergo differentiation. Cells that are triggered to undergo differentiation initially respond to extracellular signals by turning on the expression of various genes. The proteins produced from these genes cause a phenotypic change in those cells. In other words, the cells appear to be morphologically distinct and different to the HSCs. Three distinct populations are evident at this stage: erythromegakaryocytic progenitor, myeloid progenitor and the lymphoid progenitor cells. The descendents of these progenitor cells form distinct lineages of cells. These progenitor cells will then undergo another series of developmental changes (i.e., division, followed by differentiation), some of which will occur within the bone marrow, while others will occur in different somatic tissues.

THE MYELOID LINEAGE

Erythromegakaryocyte progenitor cells form two distinct lineages: the erythroid lineage and the megakaryocyte lineage. The megakaryocyte lineage gives rise to bloodplatelets(which are important in blood clotting), while the erythroid lineage gives rise toerythrocytes (red blood cells).

Myeloid progenitor cellsdifferentiate into a number ofdistinct, circulating cell types, includingneutrophils,eosinophils,basophils,mast cells, monocytes/macrophages and dendritic cells. The majority of these cells mature in the blood itself, after their precursors have migrated out of the bone marrow.

Three major groups of cells within the myeloid lineage are phagocytic. These are the granulocytes (neutrophils,basophilsandeosinophils),macrophagesand thedendritic cells.

Macrophagesare avidly phagocytic and are able to migrate out of the circulatory system to various parts of the body (tissue spaces). After ingesting pathogens, macrophagesalsosecrete signalling molecules (e.g. cytokines), which serve to attract other immune cells to the sites of infection. As such, macrophages mediate inflammation.

Thegranulocytes,neutrophils,basophilsand theeosinophils, have a highly granular cytoplasm and oddly-shaped nuclei. The cytoplasmic granules (vesicles) contain various enzymes and other molecules that can be distinguished with cellular stain. Hence, the vesicles in basophils can be visualised using cellular stains that react to basic (alkaline) pH conditions. Neutrophils are the most abundant type of white blood cell in mammals. Basophils and eosinophils are important in the immune reactions against particles that are too large to be ingested by phagocytes (e.g. parasites).

Dendritic cellsare so-called because they resemble the dendrites of the nervous system. They have a large number of finger-like projections (filopodia). Dendritic cells are migratory phagocytes, but the main difference between dendritic cells and the neutrophils/macrophages is that while the latter are concerned with destroying the ingested matter, dendritic cells perform another, rather incredible, function. They are capable of displaying, on their surfaces, small bits of the foreign matter that they have ingested. Dendritic cells are like messy eaters, leaving crumbs of their meals on their faces! At a cellular level, the ingested foreign matter is broken down by digestive enzymes within phagolysosomes (digestive vesicles). In the cytoplasm, short fragments of amino acids produced from the breakdown of the foreign matter (at this stage, these fragments are referred to as antigens) are then loaded on to specific receptors known as the Major Histocompatibility Complex (MHC) proteins. MHC proteins are highly variable receptor proteins that were initially identified as transplantation antigens. The MHC proteins that are complexed (mixed) with the antigens are shuttled to the dendritic cell's plasma membrane, where they are displayed to the extracellular environment. The antigen-MHC complex are recognised byT cells(see below), which then mount an appropriate adaptive immune response. Through this process, dendritic cells are able to convey their encounters with potential pathogen to the 'effector cells' of the immune system (e.g.T cellsandB cells). Since these dendritic cells present antigens to cells of the adaptive immune system, the dendritic cells are also known as Antigen Presenting Cells (APCs).

THE LYMPHOID LINEAGE

Lymphoid progenitor cells give rise to thelymphocytes and Natural Killer (NK) cells. The lymphocytes undergo further differentiation: one group of lymphocytes remain in the bone marrow and develop into B-lymphocytes (B cells), while the other group migrates to the thymus gland and matures into T-lymphocytes (T cells). Each B- and T-cell expresses a unique receptor that recognises foreign material (collectively referred to as antigen). The receptor on B cells is also known as an antibody. When a B cell receptor recognises an antigen, that B cell will undergo rapid cell division to produce a large number of clones (clonal B cells). Some of those clonal cells will remain in the spleen as memory B cells (for future encounters with the same antigen), while the remaining clones mature into plasma cells. In plasma cells, the antibody (which was originally) a cell surface receptor, becomes modified and is then secreted into the bloodstream (soluble antibodies). When T cells recognise foreign antigen, they will also become activated and undergo mitotic division. The activated T cell then undergoes a complex differentiation process: one group of activated T cells (called CD8 cytotoxic T cells) acquire the ability to identify and destroy pathogen-infected host cells. Another group (called CD4 helper T cells) interact with B cells to help them produce antibodies. Indeed, there are a variety of helper T cells, known as CD4TH1, CD4TH2 and CD4TH17. They appear to have specific roles in mediating adaptive immune responses. Another group of activated T cells is the regulatory T cells, which suppress immune responses. NK cells are closely related to B- and T-cells, but unlike to latter, do not rearrange their immunoglobulin genes to generate highly diverse receptors. NK cells are important in the removal of virus- and intracellular pathogen-infected cells and also in the removal of tumours.


Note: CD is an acronym for Clusters of Differentiation. It refers to a group of cell surface proteins on vertebrate blood cells that are recognised by specific monoclonal antibodies. The presence or absence of specific CD markers enable scientists to identify cell types in a population.

sham.nair@mq.edu.au
shamnair@gmail.com

Sham Nair 2014