Development of immunity

1. Presenter:
Md. Waseque Mia
Assistant Professor
Department of Biochemistry & Molecular Biology
Shahjalal University of Science and Technology
Sylhet-3114, Bangladesh.
Development of Immune System

2. Immune defense
Innate
(nonspecific defense)
Surface barriers
• Skin
• Mucosal membrane
Internal barriers
• Phagocytes
• Fever
• NK cells
• Inflammation
Adaptive
(specific
defense)
Humoral Immunity
• B cells
Cellular Immunity
• T cells

3. Pathogen-
associated
molecular
patterns

4. Development of the Immune System
@The body’s capability to react to antigens depends
on a person’s age, type of antigen, maternal
factors, and the area of the body affected.
@The body’s ability to defend against antigens
varies throughout the lifespan.

5.  Neonates are physiologically immunodeficient, meaning both
their innate and adaptive immunological responses are greatly
suppressed.
 Early in life, the immune system is not mature enough to fight off
pathogens and must depend on antibodies from the mother.
 Infants respond well to protein antigens but not as well to
glycoproteins and polysaccharides.
 In neonates, opsonic activity and the ability to activate the
complement cascade is very limited.
 Due to which phagocytic activity is also greatly impaired in
newborns.
Immunology in Newborns

6.  After 24 months of age, a child can defend well against
glycoproteins and polysaccharides.
 Although the number of total lymphocytes in newborns is
significantly higher than in adults, the cellular and humoral
immunity is impaired.
 Antigen-presenting cells in newborns have a reduced capability
to activate T cells, proliferate poorly, and produce very small
amounts of cytokines like IL-2, IL-4, IL-5, IL-12, and IFN-Ƴ.
 This limits the capacity of these cells to activate the humoral
response and the phagocytic activity of macrophages.
 B cells develop early in gestation but are not fully active.
Immunology in Newborns

7.  The lymphoid vs. myeloid model describes the process of
lymphopoiesis from pluripotent hematopoietic stem cells.
 These give rise to prolymphocytes and finally common lymphoid
progenitors, which can become NK cells, B cells, dendritic cells,
and other immune system cells.
 Hematopoiesis is the process by which all mature blood cells are
produced.
Immunology in Newborns

8. Hematopoiesis

9. Immunity During Adolescence
 During adolescence, the human body undergoes physical,
physiological, and immunological changes, triggered and
mediated by various hormones.
 Depending on the sex, testosterone or 17-β-oestradiol act on
males and females respectively, starting at around age 12 for boys
and 10 for girls.
 There is evidence that these steroids act directly not only on the
primary and secondary sexual characteristics, but also affect the
development and regulation of the immune system.
 Pubescent and post-pubescent females and males are at
increased risk for autoimmune disorders.
 There is some evidence that cell surface receptors on B cells and
macrophages may detect sex hormones in the system.

10. Aging and the Immune System
 Immunosenescence refers to the gradual deterioration of the
immune system brought on by aging.
 Hematopoietic stem cells diminish in their self-renewal capacity,
due to the accumulation of oxidative damage to DNA by cellular
metabolic activity and shortening of telomeric terminals of
chromosomes.
 Reducing the supply of leukocyte progenitors.
 The number and function of phagocytes, natural killer (NK) cells,
and dendritic cells decline with age.
 The functional capacity of T-cells declines with age.

11. T cell maturation, activation and differentiation

13. T cell maturation, activation and differentiation
 T cell is a type of lymphocyte which develops in the thymus
gland and plays a central role in the immune response.
 T cells can be distinguished from other lymphocytes by the
presence of a T-cell receptor on the cell surface.
 These immune cells originate as precursor cells, derived from
bone marrow and develop into several distinct types of T cells
once they have migrated to the thymus gland.

14. The pathway of T cell development
T cells...precursors are born in the bone marrow and “educated” in
the thymus.

15. T cell maturation
Maturation of thymocytes into mature T cells occur in distinct stages:
 Changes in the status of the T-cell receptor genes
 Expression of the T- cell receptor protein
 Production of other T-cell surface glycoproteins (essential for
receptor’s full function, such as CD4, CD8 and CD3 complex).
What allows T cell maturation?
 Direct contact with thymic epithelial cells
 Influence of thymic hormones (thymosin)
 Growth factors (cytokines, CSF)

16. Two-step Selection Process of Thymocytes
 Positive Selection: permits the survival of only
those T-cells whose TCRs recognize self-MHC
molecules  generation of a self-MHC-restricted
repertoire of T cells.
 Negative Selection: eliminates T cells that react too
strongly with self-MHC or with self-MHC plus self-
peptides  generation of a T-cell repertoire
that is self-tolerant.
How adaptive immune cells distinguish between self and non-self?
Answer lies in the processes of positive and negative selection.

17. Phenotypic Variations of T-cell during maturation
After T cells enter the thymus they begin to proliferate and differentiate
into what will be the T cells.
Stage 1 ( early thymocytes):
 These are the cells which enter the subcapsular region of the
thymus, arriving as pre-T cells from the bone marrow. (progenitor
cells).
 In this region, progenitor cells interact with thymic stromal cells,
they get signaled to proliferate, within a week they express certain
T-cell specific glycoproteins, such as: CD44 (adhesion molecule),
CD25 (receptor for IL-2).
 At this stage, they do not express TCR complex or the co-receptors
CD4 & CD8.
 These cells develop into large, actively proliferating, self-renewing
lymphoblasts which generate the thymocyte population.
 They are 3% of the cells in the thymus.

18. Stage II (Intermediate) thymocytes:
 Expressing CD1+, CD44-, CD25-
 At this stage, the cells develop the CD3:TCR complex, CD4 and CD8.
 Therefore the cells are CD3+, CD4+, CD8+.
 Genes encoding the TCR α-chain are rearranged in this stage.
 They are about 80% of cells in the thymus.
Stage III (mature) thymocytes.
Show major phenotypic changes;
 Loss of CD1
 cell surface CD3 is associated with high density by TCR
 mature T cells express either CD4 or CD8

21.  The central event in the generation of both humoral and
cell-mediated immune responses is the activation and
clonal expansion of TH cells.
 Interaction of a TH cell with Ag initiates a cascade of
biochemical events that induces the resting TH cell to
enter the cell cycle, proliferating and differentiating into
effector cells or memory cells.
TH -Cell Activation

22. TCR Engagement Initiates Multiple Signaling Pathways
Overview of Common Themes in Signal Transduction
(hydrophobic)

25. Multiple Signaling Pathways Are Initiated by TCR Engagement
ITAM: immunoreceptor tyrosine-based activation motif

28. Activation of the
small G protein, Ras

29. Naïve T cells require 2 distinct signals for activation and
proliferation into effector cells.
o Signal 1: the initial signal, is generated by interaction
of an antigenic peptide with the TCR-CD3 complex.
o Signal 2: a subsequent Ag-nonspecific co-stimulatory
signal, is provided by interactions between CD28 on
the T-cell and members of the B7 family on the APC.
Co-stimulatory Signals Are Required for
Full T-cell Activation

31. TH-cell Activation Requires a Co-stimulatory Signal
Provided by APCs
CD28 is expressed by both
resting and activated T cells.
B7 (B7-1 and B7-2) are
constitutively expressed on
dendritic cells, and induced
on activated macrophages
and activated B cells.
CTLA-4 is expressed
on activated T cells.
B7-1 (CD80)
B7-2 (CD86)
(CD152)
CD28 & CTLA-4 act antagonistically.
+
-

32. Clonal Anergy (Unresponsiveness):
 inability of cells to proliferate in response to a peptide-
MHC complex.
 If a resting TH cell receives the TCR-mediated signal (signal 1)
in the absence of a suitable co-stimulatory signal (signal 2),
the TH cell become anergic.
 In the presence of both signal 1 and signal 2, clonal
expansion results.
Clonal Anergy Ensues if a Co-stimulatory Signal Is Absent

33. Clonal Anergy Ensues if a Co-stimulatory Signal Is Absent
Signal 1 without signal 2 produces ANERGY

34. • Superantigens, a class of antigens, result in excessive activation of the
immune system.
• Not processed by antigen presenting cells.
• Specifically it causes non-specific activation of T-cells resulting in
polyclonal T cell activation and massive cytokine release.
• SAgs are produced by some pathogenic viruses and bacteria most
likely as a defense mechanism against the immune system.
• Compared to a normal antigen-induced T-cell response where 0.0001-
0.001% of the body’s T-cells are activated, these SAgs are capable of
activating up to 20% of the body’s T-cells.
• The large number of activated T-cells generates a massive immune
response which is not specific to any particular epitope on the SAg.
• Thus undermining one of the fundamental strengths of the adaptive
immune system, that is, its ability to target antigens with high
specificity.
What is Super-Antigens???

35. Superantigen-mediated Crosslinkage of
TCR and Class II MHC Molecules
Exogenous superantigens :
exotoxins secreted by G(+)
bacteria, e.g., staphylococcal
enterotoxin A & B (SEA, SEB).
Endogenous superantigens:
cell-membrane proteins
encoded by certain viruses
that infect mammalian cells,
e.g., mouse mammary tumor
viral (MMTV) protein.
Viral or bacterial proteins that bind simultaneously
to particular Vβ sequences of TCR and to the α chain
of a class II MHC molecule – induce polyclonal T-cell
activation & proliferation

36. GOAL:
1. Regulation of T cell numbers,
2. Removal of “turned off” T cells,
3. Deletion of cells with high avidity for MHC
Cell death (apoptosis)
 Programmed cell death is an essential homeostatic mechanism

37. Two Pathways to T-cell
Apoptosis
Fas-associated protein
with death domain
AICD :
activation-
induced
cell death
TCR-
mediated
negative
selection:
apoptosis-
inducing
factor
apoptotic
protease-
activating
factor 1

38. T cell differentiation:
• Remember: Naïve T cells continually re-circulate between the
blood and lymph system search for appropriate antigen.
• Once activated (Remember signal 1 and 2) Primary response
where T cells proliferate and differentiate into effector and
memory T cells.
• CD4 effector T cells can form two subpopulations based on
cytokine production: TH1 subset (IL-2, IFN-γ) and TH2 subset (IL-4,
IL-5, IL-10).
• TH1: associated with cell-mediated functions inflammation
(delayed-type hypersensitivity, activation of Macrophages and
CD8 T cells);
• TH2: associated with B-cell activation.

40. B cell maturation, activation and differentiation

41. Overview of B-cell Development
Sites of B-cell maturation –
• before birth:
 yolk sac
 fetal liver
 fetal bone marrow
• after birth:
 bone marrow

42. The discovery of B cell immunity
Studies on the function of the bursa of Fabricius, a lymphoid organ in the cloacal
region of the chicken (1954 - Bruce Glick, Ohio State University)
Bursectomy – no apparent effect
Bursectomised chickens were
later used in experiments to
raise antibodies to Salmonella
antigens
None of the
bursectomised chickens
made anti-Salmonella
antibodies
 Bursa was later found to be the organ in which antibody producing cells developed
–antibody producing cells were thereafter called B cells.
 Mammals do not have a bursa of Fabricius

43. Origin of B cells and organ of B cell maturation
Transfer marked foetal
liver cells
No Mature
B cells
Normal bone marrow
Defective bone marrow
Mature marked
B cells
in periphery
 B cell development starts in the foetal liver.
 After birth, development continues in the bone marrow.

44. B cell development in the bone marrow
 Bone Marrow provides a Maturation & Differentiation Microenvironment
for B cell development.
B Regulates construction of an antigen receptor
Ensures each cell has only one specificity
B
Checks and disposes of self-reactive B cells
B
Exports useful cells to the periphery
B
Provides a site for antibody production
B

45. B-cell Activation, Proliferation and Differentiation
Occur in a Peripheral Lymph Node

46. Bone marrow stromal cells nurture developing B cells
Types of cytokines and cell-cell contacts needed at each stage of
differentiation are different.
Secreted Factors
-CYTOKINES
2. Secretion of cytokines by stromal cells.
B
Stromal cell
1. Specific cell-cell contacts between stromal cells and developing B cells
Cell-cell contact

47. Cytokines and cell-cell contacts at each
stage of differentiation are different
Early
pro-B
Receptor
Tyrosine
kinase
Stem cell
factor
Cell-bound
growth
factor
VLA-4
(Integrin)
Stem
Stromal cell
Cell adhesion
molecules
VCAM-1
(Ig superfamily)

48. Early
pro-B
Interleukin-7
receptor
Stromal cell
Late
pro-B Pre-B
Interleukin-7
Growth factor
Cytokines and cell-cell contacts at each stage
of differentiation are different

49. Peripheral
Stages of B cell development
Stem Cell Early pro-B cell Late pro-B cell Large pre-B cell
Small pre-B cell Immature B cell Mature B cell
Each stage of development is defined by rearrangements of IgH chain
genes, IgL chain genes, expression of surface Ig, expression of adhesion
molecules and cytokine receptors.

50. pattern recognition receptors (PRRs)
Two Distinct Signals for B-Cell Activation

51. Signal Transduction Pathways and the
Activation of B Cells
 Compartmentalization of function within receptor subunits.
 Activation by membrane-associated Src family protein tyrosine
kinases (Lyn, Blk, and Fyn).
 Assembly of a large signaling complex with protein-tyrosine-
kinase activity (Syk).
 Recruitment of other signal-transduction pathways.
 Changes in gene expression.

52. Signal Transduction Pathways
Activated by the BCR

54. Sequence of Events in B-Cell Activation by a
Thymus-Dependent Ag

56. The B-Cell-Co-receptor Complex Can Enhance B-
Cell Responses: TAPA-1 (CD81), CR2 (CD21), and CD19
ITIM: immunoreceptor
tyrosine inhibitory motif

57. 1. Affinity maturation
2. Class switch
3. Formation of plasma cells and memory cells
Three Important B-cell Differentiation Events
Take Place in Germinal Centers

58. Cytokines Affect Proliferation and Class Switching of B Cells
During the Differentiation of B Cells into Plasma Cells

59. B cells play an important role in multiple aspects of immunity……..how?
• B cell-derived cytokines, including lymphotoxin, are essential for the ontogenesis,
homeostasis and activation of secondary lymphoid organs, as well as for the
development of tertiary lymphoid tissues.
• Other B cell-derived cytokines, such as interleukin-6 (IL-6), interferon-γ and tumor
necrosis factor, influence the development of effector and memory CD4+ T-cell
responses.
Lymphotoxin (previously
known as tumor necrosis
factor-beta) is a lymphokine
cytokine. It is a protein that
is produced by Th1 type T-
cells and induces vascular
endothelial cells to change
their surface adhesion
molecules to allow
phagocytic cells to bind to
them.
……by producing various Cytokines

60. THANK YOU