Chapter 2

Cells, Tissues, & Organs of The Immune System

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SUMMARY
T cell differentiation in thymus
Most cells of the immune system derive from hemopoietic stem cells. The primary lymphoid
organs in mammals are the thymus and bone marrow, where lymphocyte differentiation occurs.
Phagocytic cells are found in the circulation as monocytes and granulocytes. Monocytes
differentiate into macrophages that reside in tissues (e.g. Kupffer cells in the liver). Neutrophils are
short lived phagocytes present in high numbers in the blood and at sites of acute inflammation.
Eosinophils, basophils, mast cells, and platelets, together with cytokines and complement,
take part in the inflammatory response.
NK cells recognize and kill virus-infected cells and certain tumor cells by inducing apoptosis.
Antigen-presenting cells link the innate and adaptive immune systems and are required by T cells
to enable them to respond to antigens.
Lymphocytes are heterogeneous phenotypically, functionally, and morphologically.
B lymphocytes and T lymphocytes express specific antigen receptors called the B cell receptor
(BCR) and T cell receptor (TCR) respectively.

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There are three major subpopulations of T cells which have helper, cytotoxic and regulatory
activities (TH,TC and Treg).
B cells can differentiate into antibody-secreting plasma cells and memory cells.
T cells developing in the thymus are subject to positive and negative selection processes.
Mammalian B cells develop mainly in the fetal liver and from birth onwards in the bone marrow.
This process continues throughout life. B cells also undergo a negative selection process at the site of
B cell generation.
Lymphocytes migrate to, and function in, the secondary lymphoid organs and tissues.
Secondary lymphoid organs and tissue protect different body sites – the spleen responds to blood
borne organisms; the lymph nodes respond to lymphborne antigens; and the mucosa-associated
lymphoid tissue (MALT) protects the mucosal surfaces. Nose, GI ...
Most lymphocytes recirculate around the body; there is continuous lymphocyte traffic from the
blood stream into lymphoid tissues and back again into the blood via the thoracic duct and right
lymphatic duct.

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Outline

• Cells of the Immune System

• Anatomy & Functions of Lymphoid Tissues & Organs

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 Cells of the
Immune System

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KEY CONCEPTS ABOUT IMMUNE CELLS

1. The principle cells of the immune system: Activated T cell turns

from naiive into effector
Antigen-presenting cells  Lymphocytes => Effector cells
2. All immune cells are derived from “Hematopoietic stem cells”
in Bone Marrow (BM) (& Fetal liver during fetus).
3. Immune cells are divided into two major lineages:
=> Lymphoid & Myeloid
=> Multiple cell types => express distinct “Surface molecules (markers)”
=> Classification
4. Development and differentiation of different cell types
depend on “Cell Interactions and Cytokines”.
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CELLS OF THE IMMUNE SYSTEM-I

1. Originated from
Bone Marrow (BM)

2. Two major lineages:

- Lymphoid
- Myeloid

3. NK cells
- Large Granular
Lymphocytes (LGL)

NK => LGL
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Cells of the Immune System-II T lymphocytes are
first derived from
BM and further
educated in Thymus
for maturation.
immature

Megakaryo
cyte never
leaves BM

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CELLS OF INNATE IMMUNITY-I

1. Innate immune cells are derived from Bone Marrow.

2. Their primary function is to identify and kill microbes.

Antigen-presenting cells (APCs) additionally function
to present Ag to and activate lymphocytes. Macrophages and dendritic
cells are the only cells that
can phagocyte AND present

3. Innate immune cells recognize the common microbial

structures PAMPs through Pattern-Recognition
Receptors (PRRs) -limited diversity.
E.g. LPS of gram negative
It doesn’t see E. Coli or salmonella,
it sees the pattern, not specific
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CLASSES OF INNATE IMMUNE CELLS
Innate immune cells are classified
as following:
- Monocyte/Macrophage
- Dendritic cell (DC)
- Polymorphonuclear
granulocyte (PMN;
Neutrophil, Eosinophil,
Basophil)
- Mast cell
- NK cells (lymphocyte) Lymphoid origin
=> Killing virus-infected cells
& tumors Only if MHC 1 is not present on the cell

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 DEVELOPMENT OF MONOCYTES &
GRANULOCYTES
1. Myelopoiesis – Development
of myeloid cells.

2. Cytokines from stromal

cells, myeloid, & lymphoid
cells are involved in this
process. Types of cytokines
determine destination

CFU: colony forming units

GEMM: granulocytes, erythrocytes, monocytes,
and megakaryocytes
GM-CSF : granulocyte–macrophage colony-
stimulating factor
TP: Thrombopoietin
B: basophil
BFU-E: erythrocytic burst-forming unit
DC and macrophage are
DC: dendritic cell from same origin!! (There’s a
Epo: erythropoietin DC from another origin too)

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MATURATION OF MACROPHAGES

Activated Macro
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KEY CONCEPTS OF MONOCYTES/MACROPHAGES

1. Relatively long-lived and distributed

throughout the whole body.

2. Engulf and kill pathogens by phagocytosis.

Scavenger: 3. Express various receptors to recognize

eats old different pathogens, e.g. PRR, Scavenger
dead of my
own tissue receptor,….etc. Up to 1000 different types
PRR: pattern recognition receptor
Histoplasma capsulatum in macrophage
4. Trigger inflammation and Antigen presentation

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pinocytotic vesicles
(PV), lysosomal
granules (G),
mitochondria (M),
and isolated rough
endoplasmic
reticulum cisternae
(E)

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PHAGOCYTOSIS BY INNATE IMMUNITY (1)

Bacteria that’s
catalase positive
prevents killing
by H2O2

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 PHAGOCYTOSIS BY INNATE IMMUNITY (2)
From TH cells
For LPS

Amplification

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 Ag-presenting cells (APCs) link the innate
& adaptive immune systems

DC presents MHC2 Ag
to turn TH from
naive into effector

Macrophages for
helping killing

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 POLYMORPHONUCLEAR
GRANULOCYTES: NEUTROPHILS
1. Comprise over 95% of
granulocytes
2. Short-lived (2-3 days)
3. Multi-lobed nucleus
4. Kill pathogens by
phagocytosis & releasing
cytotoxic substances.
Macrophages can divide
outside, neutrophils can’t
50 - 70% of WBCs
Segments = mature cells
Bands = immature cells
Bands in blood indicate
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 BASOPHILS & MAST CELLS: CRITICAL
FOR IMMUNITY AGAINST PARASITES

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 EOSINOPHILS

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 DENDRITIC CELLS (DCS) AS AG-PRESENTING
CELLS (APCS)

Once it eats antigen

and becomes mature,
it can’t phagocytose
anymore

Doesn’t do
FDC:Follicular DC
phagocytosis
Doesn’t show Ag on
MHC2, presents as it is
because B cell sees it
as it is!

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 KEY CONCEPTS OF DENDRITIC CELLS (DCS)

1. Most effective Ag-presenting cells linking innate and

adaptive immunity Because it activates T cells

2. High MHC-II expression on DCs

3. Several types of DCs: In tissue and does phagocyotsis

(1) Myeloid DCs (also known as conventional DCs)
(2) Lymphoid DCs => Plasmacytoid DCs Helps in presenting Ag from conventional DC,
not found in tissue
(3) Lymphoid organ-specific DCs:
Follicular DCs in Lymph nodes (lacking MHC-II)
(4) Interdigitating Dcs in Lymph nodes & Thymus
Presents my own Ag, allows T cells to pass by, if T cell
binds and gets activated, DC sends signal of death
Negative selection!
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MYELOID AND PLASMACYTOID DENDRITIC CELLS (DCS)

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 MIGRATION OF ANTIGEN-PRESENTING
CELLS (APCS) INTO LYMPHOID TISSUES

Langerhans’ cells (DC) are found in the

epidermis and in mucosa , they are rich
in MHC class II molecules, and carry
processed antigens.
(HEV, high endothelial venule)
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Naturally kills,
it doesn’t need
anything to
activate it, it
needs
something to
inhibit it

Binding to any
cell causes it
to kill it!

What inhibits
it? MHC1

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CELLS OF ADAPTIVE IMMUNITY
1. Lymphocytes are the key players of the adaptive immunity.

2. Lymphocytes are able to specifically recognize and respond to diverse

antigens.
=> Antigen (Ag) receptors on lymphocytes
=> Specificity (Clone), Diversity (Repertoire: total number of Ag-specific
lymphocytes in an individual; 107-9), & Memory

3. Lymphocytes are classified into three major groups:

- B cells => Antibodies => Humoral immunity Because they produce antibodies
not kill directly
- T cells => Multiple subtypes => Cell-mediated immunity & Regulate other
Because they themselves go and kill
immune cells
- NK cells => Innate immunity
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 CLASSES OF
LYMPHOCYTES
1. B cells => Plasma cells
* Neutralization (prevents attachment
=> Abs = no infection)
* enhance phagocytosis (opsonization)
* activates complement
2. T cells:
- T helper cells
- T cytotoxic cells
- T regulatory cells
=> suppress immune MHC1

responses
3. NK cells
4. Subtypes in each class
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 T cells vs B cells

Proteins fats

Only TH

Only CTL

CD40 ligand on T cell

T cell binds to activate
B cell (to amplify
signals) without it no
humoral immunity

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 Even if they bind, without it no activation

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 LYMPHOCYTES

Large so NK

Small Lymphocytes Large Granular Lymphocytes

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 PLASMA CELLS-AB SECRETION

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 FUNCTIONAL T CELL SUBSETS

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 THE NOBEL PRIZE IN PHYSIOLOGY OR
MEDICINE 2011

Bruce A. Beutler Jules A. Hoffmann Ralph M. Steinman

The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to
Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the
activation of innate immunity" and the other half to Ralph M. Steinman
"for his discovery of the dendritic cell and its role in adaptive immunity".
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Home study IDENTIFICATION OF CELL POPULATIONS
Questions on assignment

1. Molecules on or in cells
=> Identification &
Classification
e.g. CD3, CD4, CD8….

2. Methods:
(1) Immunofluorecence

CD: Cluster of Differentiation

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(2) Flow Cytometry & Sorting

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 (3) ELISPOT

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 IDENTIFICATION & ISOLATION OF CELL POPULATIONS

Isolation of lymphocyte subpopulations – panning Cell separation by immunomagnetic beads.

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 Anatomy & Functions of
Lymphoid Tissues & Organs

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Primary lymphoid organs:
BM & Thymus
=> Lymphocyte development,
selection, & maturation.

2nd lymphoid organs:

Lymphoid nodes & Spleen
Both primary
=> Lymphocyte activation & and secondary

effector functions

BM
 Other immune cells
Eg. DCs, Macrophages,
PMNs
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 THE LYMPHATIC
SYSTEM

Link to the blood

circulation system

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BONE MARROW
1. The site of generation of
all immune and blood cells
<= Hematopoietic Stem Cell

2. Provides Cell-cell
interactions and Cytokines
for the development of
all immune cells.
<= Stromal reticular cells
& other cells

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 THYMUS-I
1. The site of T cell maturation =>
Thymus-dependent (T)
lymphocytes or T cells =>
Thymocytes: developing T cells in thymus

2. Upper anterior thorax (above the heart).

3. Multiple lobules => Each has

Outer Cortex => Dense T cells
Inner Medulla => Sparse T cells
Other cells: thymic epithelial
cells (TECs), DCs, Macrophages
=> Cell-cell interactions and
Cytokines
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 CELL MIGRATION TO AND WITHIN THE THYMUS

High conc
postcapillary venules (PCVs)

Double negative

Low conc

Marker

subcapsular region where they

HEVs at the corticomedullary junction.
actively proliferate and differentiate
into double positive

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 THYMUS-II
Subcapsular epithelial cells that produce
IL-7 (nurse cells) sustain T lymphoblast
proliferation in the outer cortex.
Positive
Developing T cells interact with the selection:
- it has to
cortical epithelial network where they are recognize MHC
positively selected. Apoptotic cells are - it can’t
recognize my
phagocytosed by macrophages present in own cells
the deep cortex and in the medulla. TCR+
thymocytes co-expressing CD4 and CD8
undergo the process of negative
selection by interacting with a variety of
antigen-presenting cells (APCs), such as
dendritic cells, interdigitating
cells, macrophages, and epithelial cells. B cell only has
negative
T cells that have survived the selection selection
processes are exported from the thymus because it
doesn’t need
via high endothelial venules (HEVs) and MHC
lymphatic vessels.

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 EXPRESSION OF HUMAN T CELL MARKERS
DURING DEVELOPMENT

Terminal deoxynucleotidyltransferase (TdT)

CD25 is in the immature T cell, but not

in the mature , it’s a marker for B cell

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 T CELL
DIFFERENTIATION IL7

IN THE THYMUS

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 B CELL DEVELOPMENT IN THE
BONE MARROW

Negative selection, check if it

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recognized my own antigens
 2ND LYMPHOID ORGAN-LYMPH NODE (LN)

LNs => Small nodular

organ => Body
=> Lymphocyte activation

Lymphocytes =>
Segregated in the
distinct regions of LN

The outer cortex

=> B cell zone (follicle)
=> Germinal Center (2nd
follicle)=>B cell activation

The inner region

=> T cell zone

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 LYMPH NODE (LN) SECTION

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 STRUCTURE AND FUNCTION OF THE
GERMINAL CENTER
Without T cell no class
switching or memory,
Mutations that have only plasma cell or IgM
higher affinity are
selected by
follicular cell

IgM to IgE or IgA ...

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 SPLEEN

1. The site of immune

responses to blood Ags
=> A filter of blood

2. White pulp => T cell & B

cell zones
Marginal zone (MZ)
Red pulp (RP)

3. T cells => periarteriolar

lymphoid sheaths
B cells => follicle
=> marginal zone

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 MUCOSA-ASSOCIATED LYMPHOID ORGANS (MALT)

GI, nose

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 MIGRATION OF
LYMPHOCYTES-I

1. In LN, naïve lymphocytes

 HEVs
Rolling => Adhesion
=> Transmigration
Adhesion molecules for
cell-cell interactions

2. In peripheral infection
sites, effector
lymphocytes  blood
vessels
E or P
selecting
shows in
site of
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 MIGRATION OF LYMPHOCYTES-II

Selectin and integrin appear due to

macrophage at site of inflammation

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 ACTIVATION OF LYMPHOCYTES

In general, lymphocyte
Not anytime
activation requires “Two
we see an Signals” (from Antigen
antigen we presenting cells (APCs))
can bind,

Signal 1:
Ag  Ag receptor on
lymphocytes (T & B)

Signal 2:
Molecules (innate
response)
Costimulatory receptors
on lymphocytes

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 SUMMARY
1. Immune cells are derived from “Bone Marrow (BM)”.
T-lineage progenitor cells are first derived from BM and move to
“Thymus” for maturation.

2. Key cells in innate immune responses include

- Macrophage & DCs => Ag presentation
- Granulocytes (PMNs)
- NK cells

3. Key cells in Adaptive immune responses include

- B lymphocytes => Ab => Extracellular bacteria
- Several T cell types => Fight intracellular microbes &
Regulate the program of an immune response

4. Primary lymphoid organs (BM & Thymus)=> Immune cell development

2nd lyphoid organs (LN & Spleen)=> Concentrate Ag from tissues
or blood for lymphocyte activation.
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 Critical Thinking
Immunodeficiencies can tell us a lot about the way the immune
system functions normally. Mice that congenitally lack a thymus
(and have an associated gene defect that produces hairlessness),
termed ‘nude mice’, are often used in research.

1 What effect would you expect this defect to have on numbers and
types of lymphocytes in the blood? How would this affect the
structure of the lymph nodes? What effect would this have on the
ability of the mice to fight infections? No T cells, but
Occasionally adult patients develop a tumor in the thymus there’s B cells

(thymoma) and it is necessary to completely remove the thymus T zone would get
Old age have smaller and
produced gland.
atrophy
already enough 2 What effect would you expect adult thymectomy to have on the
T cells
ability of such patients to fight infections?
B cell inefficient because it needs T helper and CT

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 With the development of modern techniques in molecular biology, it
is possible to produce animals that completely lack individual genes.
Such animals are called ‘gene knockouts’. Sometimes these
knockouts can have quite surprising effects on development, and
sometimes only minor effects. Others, like the immunodeficiencies,
are very informative. Based on the information provided in Chapter
2, what effects would you expect the following ‘knockouts’ to have
on the development of leukocytes and/or lymphoid organs?
3 RAG-1? (RAG-1 and RAG-2 genes are involved in the
recombination processes that generate antigen receptors on B and T
cells.) No receptor, no B or T, no adaptive immunity . No innate immunity (t cell
activate macrophage, complement system needs antibody)
can’t

4 Interleukin-7? No proliferation of T cell

5 The β7-integrin chain? Responsible for second signal , without it no binding

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