Cells of the Immune System

The immune system is the body’s defense against infection and diseases, and consists of two major arms - the innate
immune system and the adaptive immune system. Both parts are comprised of many cell types, each with its own
specialty, that work together to fight off disease and help maintain the body’s health.
All the cells of the immune system develop from hematopoietic stem cells located in bone marrow. The hematopoietic
stem cells give rise to lymphoid and myeloid progenitors - each of which differentiate into a variety of cell types.
The myeloid lineage consists mostly of innate immune system cells, whereas the lymphoid progenitors differentiate
into three categories of cells: B cells, T cells, and Natural Killer (NK) cells.

Mast cell Natural Killer

cell
Memory
T cell
Neutrophil
Cytotoxic
T cell

Eosinophil

E
THE
NUM
INNATE
MI ETAIMMUNE
NNI EHT T cell
Helper
T cell
M ETSYS
SYSTEM progenitor

Basophil

E
THE
NUM
ADAPTIVE
MI EVITPA
IMMUNE
DA EHT
M ETSYS
SYSTEM

Plasma
Monocyte cell

Myeloid
B cell
progenitor
Macrophage progenitor
Lymphoid
progenitor

Memory B
cell
Dendritic
cell

Hematopoietic
stem cell
 HEMATOPOIETIC STEM CELL
SELF-RENEWAL EXPANSION
CYTOKINES CYTOKINES

Hematopoietic stem cell SCF; TPO Flt3-Ligand; SCF; TPO; IL-3; IL-6

THE INNATE IMMUNE SYSTEM THE ADAPTIVE IMMUNE SYSTEM

DIFFERENTIATING SECRETED DIFFERENTIATING SECRETED
CYTOKINES CYTOKINES CYTOKINES CYTOKINES
Myeloid IL-3; IL-6; EPO; Lymphoid IL-7
progenitor GM-CSF; G-CSF progenitor

Monocyte GM-CSF; G-CSF B cell IL-3; IL-4; IL-6; IL-7;

progenitor SCF

Macrophage IFN-γ; IL-6; IL-10; TGF-β; TNF-α; VEGF; IL-1β; Plasma cell IL-4; IL-5; IL-10;
M-CSF IL-6; IL-10; IL-12 IL-21; TGF-β; IFN-γ

Dendritic Flt3-Ligand; IL-1α; IL-1β; IL-4; IL-6; IL-10; T cell IL-2; IL-7; Notch GM-CSF; TGF-β; TNF-α;
cell GM-CSF; IFN-α; IL-4 IL-12; TGF-β; IFN-α; IFN-γ progenitor IL-4; IL-6; IL-10; IL-12

Eosinophil IL-3; IL-5; GM-CSF TGF-β; VEGF; PDGF-BB; Helper T IL-2; IL-4; IL-6; IL-12; * IFN-γ; TNF-α; TGF-β; IL-4;
TNF-α; IL-1α; IL-1β; IL-2; IL-4; cell TGF-β; IFN-γ IL-5; IL-6; IL-9; IL-10; IL-13;
IL-5; IL-6; IL-8; IL-12; IL-13 IL-17; IL-21; IL-22
Basophil IL-3; IL-6; GM-CSF; TNF-α; IL-4; IL-6; IL-13 Cytotoxic IL-2; IL-5; IL-7; IL-12 IFN-γ; TNF-α; TNF-β; IL-2;
G-CSF T cell sFas Ligand

Mast cell IL-3; IL-6; GM-CSF; TNF-α; GM-CSF; IL-3; IL-4;

G-CSF IL-5; IL-6; IL-8; IL-13

Neutrophil IL-6; GM-CSF; APRIL; RANKL; TNF-α;

G-CSF; SCF TGF- β; VEGF; IL-1α; IL-1β;
IL-6; IL-12; IL-18; IL-21
NK cell IL-15 GM-CSF; IFN-γ; TNF-α;
MIP-1α; MIP-1β; IL-5; IL-10;
IL-17; IL-22

Note - The list of the differentiating and secreted cytokines is partial.

* - Secreted by different subsets of Th cells.

The Innate Immune System

The innate immune system is the body’s first line of defense and provides a quick-yet-general immune response, while the adaptive
immune system works by detecting and eliminating specific pathogens that threaten the body. While both systems work to fight off
infection, the adaptive immune system takes much longer to respond than the innate immune system.
The activity of the cells of the innate system is based on pattern recognition receptors (PRRs) - special proteins that engage in
detecting conserved antigens of groups of bacteria and viruses. There are two types of structures that are recognized by PRRs,
pathogen-associated molecular patterns (PAMPs) that are involved in pathogen recognition, and damage-associated molecular
patterns (DAMPs) that function in recognizing damaged cells. There are several families of PRRs that include:

TOLL-LIKE RECEPTORS C-TYPE LECTIN RECEPTORS RETINOIC ACID-INDUCIBLE GENE-I

(TLRS) (CLRS), (RIG-I)-LIKE RECEPTORS (RLRS)
involved in microbial recognition which are major fungi receptors that recognize RNA viruses

Unlike PRRs, which are germline-encoded, fixed and limited in number, antigen-specific T cell receptors (TCRs) and B cell immuno-
globulins (Igs) of the adaptive immune system are the result of somatic gene rearrangements and can recognize practically any
antigen.
HEMATOPOIETIC LINEAGE OF THE INNATE IMMUNE SYSTEM
Myeloid progenitors give rise to neutrophils, eosinophils, basophils (named after their staining characteristics), mast cells and
monocytes, which further differentiate into dendritic cells (DCs) and macrophages.
Neutrophils, together with eosinophils and basophils, are granulocytes (cells containing granules), that belong to a family of
leukocytes known as polymorphonuclear (PMN) due to their multi-lobed nuclei. Neutrophils are the most common phagocytes,
being the first to arrive at the site of tissue damage. They specialize in phagocytosis and digestion of pathogens, especially bacteria,
throughout the body.
Eosinophils possess kidney-shaped, lobed nuclei that release the content of their granules in order to extracellularly digest pathogens,
especially parasites, as well as secreting a variety of cytokines and growth factors that affect other cells of the immune system.
Although they are the least common granulocytes, basophils are the largest of the granulocytes, exhibiting bi-lobed nuclei and
histamine-rich granules. Basophils are involved in a variety of inflammatory reactions, including reactions associated with allergic
symptoms and are an important source of IL-4, a cytokine responsible for inducing the differentiation of naïve to mature T helper
(Th) cells.
Mast cells are tissue-resident granulocytes, secreting histamine and heparin, among other factors, which are involved in the
defense against parasites, and also in wound healing and angiogenesis.
Monocytes, the largest of the white blood cells, give rise to the two other types of professional antigen-presenting cells (APCs),
dendritic cells (DCs) and macrophages.
DCs are present mostly in tissues that are in contact with the environment outside the body, such as the skin, lungs, and intestines.
Regarded as the most efficient APCs, a DCs’ main function is to process, present, and cross-present antigens to T and B cells. Upon
activation, they are also able to secrete cytokines like IL-6, IL-10, and IL-12.
Macrophages (from Greek, “makrós” and “phagein,” meaning “big eaters”) are phagocytic scavengers that engulf and process a
variety of unwanted materials that differ from healthy cells, such as cellular debris, pathogens, and cancer cells. They are tissue
residents and have specific names according to their respective location. Activated macrophages are divided into two major groups,
M1 and M2. M1 macrophages have pro-inflammatory activities, while the M2 macrophages are involved in wound healing and tissue
regeneration, as well as exhibiting anti-inflammatory properties.
NK cells are cytotoxic cells, with small granules in their cytoplasm containing perforins and granzymes, which are used to kill their
target cells. They are generated from the common lymphoid progenitor, which also produce B and T lymphocytes, but they belong
to the innate immune system. NK cells destroy cancerous and infected cells by a rapid response, without the need for antigen-
specific recognition and activation.

The Adaptive Immune System

An important feature of the adaptive immune system is the ability to provide long-term memory. This feature allows for faster and
more efficient immune response in future encounters with a specific pathogen.
HEMATOPOIETIC LINEAGE OF THE ADAPTIVE IMMUNE SYSTEM
Mature B cells, when activated, differentiate into memory cells and plasma cells that secrete pathogen-specific antibodies, which
play a central role in the protective immune response. B cells are one of three types of professional antigen-presenting cells (APCs).
MHC class I proteins are expressed constitutively on the surfaces of all nucleated cells in the body while MHC class II proteins are
typically expressed on the surfaces of certain APCs such as macrophages, B cells, and dendritic cells along with a variety of co-stim-
ulatory molecules. MHC (Major Histocompatibilty Complex) Class II cells are involved in the activation of T cells by displaying
peptide fragments of processed antigens.
Many types of T cells arise from a common T cell progenitor. Of these cells, the most commonly known are memory T cells, CD8+
cytotoxic T cells (Tc) and CD4+ Th cells. Tc cells identify and destroy cells carrying pathogen-specific antigens. Th cells, on the other
hand, secrete cytokines that regulate the immune response upon being activated by antigen-presenting cells. This action is especial-
ly characteristic of the adaptive immune system, in which Th cells enhance or suppress the activity of other immune cells. The Th
cells are further divided into several subsets, such as Th1, Th2, Th17 and Treg, each secreting a specific cytokine profile and having
a particular regulatory function of the immune response.
B plasma cells and various types of T cells are key elements of the adaptive immune system.

Communication Between Innate and

Adaptive Immune Systems
The adaptive immune system requires members of the innate system, such as DCs,
to present antigens in order to launch and direct its responses. DCs, in particular,
form a bridge between the innate and adaptive immune systems by conveying
several signals which regulate and direct the adaptive immune response. The
interaction between the two systems is not one-sided, as phagocytes and
other cells of the innate system recognize, through their FC receptors,
antibodies bound to pathogens that enable the phagocytes and other
mature cells of myeloid progeny to identify and destroy pathogens more
efficiently. As a result, these activated phagocytes support T cell responses.
Cellular cross-talk plays an important role in the adaptive-immune
response, such as in the case of naïve B cells that require stimulation by
CD4+ Th cells in order to mount an effective response to antigens. Such
cross-talk also occurs in the innate immune system when activated cells,
such as neutrophils, secrete chemokines and cytokines. This activity influenc-
es the recruitment and activation of DCs.
Thus, the two arms of the immune system work together via cellular cross-talk
and chemical signals in the form of cytokines and other secreted molecules in
order to provide the most efficient protection for the body.
Additional reading:
1. Brubaker, Sky W., et al. "Innate immune pattern recognition: a cell biological perspective." Annual review of
immunology 33 (2015): 257-290.
2. Clark, Rachael, and Thomas Kupper. "Old meets new: the interaction between innate and adaptive immunity"
Journal of Investigative Dermatology 125.4 (2005): 629-637.
3. Cruvinel, Wilson de Melo, et al. "Immune system: Part I. Fundamentals of innate immunity with emphasis on
molecular and cellular mechanisms of inflammatory response." Revista brasileira de reumatologia 50.4 (2010):
434-447.
4. Iwasaki, Akiko, and Ruslan Medzhitov. "Control of adaptive immunity by the innate immune system." Nature
immunology 16.4 (2015): 343-353.
5. Jain, Aakanksha, and Chandrashekhar Pasare. "Innate control of adaptive immunity: beyond the three-signal
paradigm." The Journal of Immunology 198.10 (2017): 3791-3800.
6. Mesquita Júnior, Danilo, et al. "Immune system-part II: basis of the immunological response mediated by T and B
lymphocytes." Revista brasileira de reumatologia 50.5 (2010): 552-580.
7. Nimmerjahn, Falk, and Jeffrey V. Ravetch. "Fcγ receptors as regulators of immune responses." Nature Reviews
Immunology 8.1 (2008): 34-47.
8. Parker, George A. "Cells of the Immune System”. In: Parker G. (eds). Immunopathology in Toxicology and Drug
Development. Humana Press, Cham, (2017). 95-201. https://doi.org/10.1007/978-3-319-47377-2_2
9. Rock, Kenneth L., Eric Reits, and Jacques Neefjes. "Present yourself! By MHC class I and MHC class II molecules"
Trends in immunology 37.11 (2016): 724-737.
10. Yatim, Karim M., and Fadi G. Lakkis. "A brief journey through the immune system." Clinical Journal of the American
Society of Nephrology 10.7 (2015): 1274-1281.

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