In the last post, we discussed about the different cellular components of the immune system or the leucocytes. We saw in details about the granulocytes like basophils, neutrophils, eosinophils and the mast cells. In this post, we shall learn a bit more about the agranulocytes derived from the myeloid progenitors and the cells derived from the lymphoid progenitors (in the next post).
Agranulocytes:
The agranulocytes are the cells derived from the myeloid progenitors, which lack the granules, unlike the granulocytes. The agranulocytes include the cells like monocytes, macrophages and the myeloid-lineage dendritic cells. The macrophages and the myeloid lineage dendritic cells are derived from the monocytes. All three are phagocytes, can present antigens and produce different repertoire of cytokines.
Let’s discuss about each of these cells:
1. Monocytes:
• Morphology:
Monocytes are amoeboid in shape with an oval to kidney shaped nucleus. They have a high nucleus to cytoplasmic ratio and many cytoplasmic vesicles. Monocytes are agranulocyte leucocyte, i.e. they lack the cytoplasmic granules. These cells constitute around 2-10% of all the leukocytes
• Location:
They are formed in the bone marrow and enter the circulation, where they remain for a very long time, e.g. 71hr in humans, and then migrate into the tissues. On migrating into the tissues, the monocytes can differentiate into macrophage or myeloid lineage dendritic cells depending on the inflammatory environment.
• Functions:
Monocytes is a part of innate immune system and helps fight against viral, bacterial, fungal or parasitic infections. Their functions include phagocytosis, antigen presentation and production of cytokines.
a. Phagocytosis:
Monocytes are highly phagocytic. They can phagocytose microbes and particles bound by Ig and/or complement (opsonization). They get mobilized to the site of invasions shortly after the neutrophils . Monocytes remain at the site of inflammation and infection for a long period of time.
b. Antigen presentation:
Monocytes phagocytose and process the antigens and load it onto the MHC molecules and present them to the T cells.
c. Cytokine production:
The monocytes also produce large amounts of cytokines such as IL-12 and interferon (IFN)-γ hence aiding the regulation of the adaptive immune responses. They can mobilize other cells to the site of infection and hence promote immune defence during infection and inflammation.
• Types:
Depending on the expression of CD14 and CD16, the monocytes can be three different subtypes:
a. Classical monocytes
The classical human monocyte (CD14++CD16− ), account for 80–90% of peripheral blood monocytes. These are also known as inflammatory monocytes. These cells can infiltrate tissues, produce pro-inflammatory cytokines, and differentiate into inflammatory macrophages. Classical monocytes express several pattern recognition receptors (PRRs) and are involved in removing micro-organisms and dying cells via phagocytosis. These cells are highly phagocytic.
b. Intermediate monocytes:
These cells constitute around 2-10% of the circulating monocytes. These monocytes, too, have proinflammatory functions and produce high amounts of IL-1β, IL-6, IL-12, and TNFα, upon stimulation. These cells present antigens and induce T-cell activation. Intermediate monocytes specifically promote proinflammatory Th17-cell responses.
c. Nonclassical or anti-inflammatory monocytes:
These cells constitute around 2-11% of the circulating monocytes. These are anti- inflammatory and work to maintain vascular homeostasis. These cells patrol the body for Damage-associated molecular patterns (DAMPs) and differentiate into tissue-resident macrophages in steady state or into anti-inflammatory macrophages during inflammation to repair damaged tissues.
• Clinical significance:
Monocyte count is a part of complete blood count and is a useful diagnostic tool. An increase in monocytes may predict the infection by a bacteria, fungus or virus.
2. Macrophages:
Macrophages were first discovered late in the 19th century by Ilya Metchnikoff. Macrophages are differentiated monocytes and have larger cells and more intracellular organelles. Like monocytes, macrophages, too, have various types of PRRs, can phagocytose and recruit other immune cells to the site of infection.
• Morphology:
As the monocyte differentiates into macrophage, the cell volume and the number of cytoplasmic granules increases. The cell shape varies depending on the tissue type in which the macrophage resides. However, the common feature is the membrane- bound lysosomes, essential for the process of the phagocytosis.
• Locations:
Monocytes differentiate into macrophages on entering a tissue. Depending on tissues of residence the macrophages have been given different names. The macrophages are called as intestinal macrophages in the gut, Kupffer cells in the liver, microglial cells in the brain and osteoclasts in bone.
• Functions:
a. Phagocytosis:
Macrophage is a phagocytotic cell and play important role in the adaptive immune response by taking up microbial antigens and processing them by proteolysis to peptide fragments
(Just for info: Watch this video where the macrophage is in action.)
b. Antigen presentation:
Macrophages express both class I and class II major histocompatibility complex (MHC) molecules and present the processed antigen through the T-cell receptor (TCR) on TH cells.
(Just for info: Read this paper titled ‘Antigen presentation the macrophage way’ to know more about the process.)
c. Synthesis of cytokines:
When activated, macrophages release cytokines and chemokines as a major component of the innate immune response. They secrete a wide range of inflammatory regulators that regulate the inflammation process. Inflammatory cytokines also help in recruiting other immune cells bringing about a larger response.
• Types:
Depending on the function, the macrophages are of two different types:
i. Classically activated macrophages or the M1-type Macrophage:
The differentiation into M1 macrophages need IFN-γ. M1 macrophages exhibit great pro-inflammatory and anti-bacterial activities. These macrophages produce large amounts of pro-inflammattory cytokines and chemokines like IL-6, IL-12, and TNF.
ii. Alternatively activated macrophages or M2-type macrophages:
The IL-4 produced by Th2 cells help differentiation of macrophages into M2 macrophages. It is also influenced by the presence of IL-10, or IL-13 and glucocorticoid hormones. These cells secrete anti-inflammatory cytokines like IL-10, the IL-1 receptor antagonist, transforming growth factor β (TGFβ) and so on. These cells have anti-inflammatory action and play a predominant role in wound healing and tissue repair.
• Clinical Significance:
The macrophages are involved in many diseases of the immune system like atherosclerosis, asthma, rheumatoid arthritis and fibrosis.
3. Dendritic cells
The dendritic cells (DC) were discovered by Ralph Steinman at The Rockefeller University in the early 1980s. They are agranulocytes and can differentiate from both the myeloid and the lymphoid progenitor cells. DCs have a large number of receptors (PRR) for pathogen-derived components which aids in the detection of invading pathogens. They are the most potent types of APC.
• Location:
Dendritic cells are present at different location. Depending on the environment the DCs are subdivided as:
– plasmacytoid DCs (pDCs): blood and in lymphoid tissues.
– conventional DCs (cDCs): reside in tissues.
– monocytes derived DCs (mDCs): under inflammatory conditions in peripheral tissues.
These cell types differ phenotypically and reside in different tissues.
• Types (or states):
The conventional DCs may be divided into two states: immature and mature.
a. Immature DC:
Immature DCs are the ones which present self or harmless antigens and bring about immune tolerance. Immature DCs are not great antigen presenters but good in capturing antigens. They have less co-stimulatory molecules expressed on surfaces.
b. Mature DCs:
When there is any infection, the DCs mature and may induce Th2 or Th1 immune responses. When mature, the other processes like antigen capturing are down regulated but antigen presentation improves greatly.
In each state, DCs have the ability to secrete different cytokine patterns, resulting in the induction of different immunological responses.
• Functions:
a. Immune survelliance:
DC patrols the body to recognize and destroy not only invading pathogens but also the tumor cells of the host. Various factors which influence differentiation and function of DCs are GM-CSF, M-CSF, Flt3, and TGF-β.
b. Phagocytosis:
These cells engulf the pathogens and break them down to partially degrade pathogen-derived proteins to yield antigenic peptides.
c. Antigen presentation:
Dendritic cells are highly potent antigen presenting cells. The antigenic peptides obtained after proteolytic degradation is then loaded onto the MHC molecules. DC possesses both MHC class I or class II molecules. The antigenic peptide–MHC complexes are then transported to the plasma membrane, and the antigen is presented to the T cells. This activates the T cells and leads to its proliferation and differentiation into effector cytotoxic T cells or helper T cells, essential for overall immune response. DCs also express ligands like CD80, CD86, that enhances the T-cell response by binding to co-stimulatory molecules on T cells. DC also produce cytokines like interleukin-12 (IL-12) which aids optimal T-cell stimulation.
d. Synthesis of cytokines:
The dendritic cells also secrete various cytokines like IL-1, 6, 7, 12, 15, 18, TNF, TGF, M-CSF and GM-CSF.
e. Immune tolerance:
DCs can maintain immune tolerance so that the effector T cells are not produced against the normal or “self” antigens. In the absence of infection, DCs continuously encounters and presents self-antigens and non-pathogenic antigens to T cells. In such conditions, there is production of immunosuppressive regulatory T cells (Tregs) is favoured. These “induced” Tregs, prevents immune response against these antigens.
(Just for info: Read more in details about the ‘Mechanisms of tolerance induction by dendritic cells.’)
• Clinical significance:
DCs are involved in the pathophysiology of various diseases like contact hypersensitivity, autoimmune diseases, cancer, etc. They can also be used as therapeutic tools in these conditions.
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These are the cells derived from the myeloid progenitors. The other group of cells are derived from the lymphoid progenitor which include B lymphocytes, T lymphocytes and natural killer (NK) cells.
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References:
Mellman (2013) Dendritic cells: master regulators of the immune response. Cancer Immunol Res. 1(3):145-9.
Karlmark et al (2012) Monocytes in health and disease – Minireview. Eur J Microbiol Immunol (Bp). 2(2): 97–102.
Geissmann et al (2010) Development of monocytes, macrophages and dendritic cells. Science 327(5966): 656–661.
Yuen-Fen (2010) Observation of dendritic cell morphology under light, phase-contrast or confocal laser scanning microscopy. Malaysian J Pathol. 32(2) : 97 – 102.
Hubo et al (2013) Costimulatory Molecules on Immunogenic Versus Tolerogenic Human Dendritic Cells. Frontiers in Immunology 4:82
Hu et al (2000) Deficient In Vitro and In Vivo Phagocytosis of Apoptotic T Cells by Resident Murine Alveolar Macrophages. J Immunol. 165 (4) 2124-2133.
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