1. Immunology Lecture 4 Development of B and T lymphocytes

2. Development of B and T Lymphocytes
Newborn has a well developed but naïve immune system
The development of B cells occurs in the Bone Marrow
The development of T lymphocytes occurs in the Thymus
During development, pre-B and pre-T lymphocytes learn to differentiate
between self and non-self antigens in a process called tolerization
Failure to differentiate between self and non-self antigens can result in
autoimmunity 2

3. Development of B lymphocytes
B cell differentiation in the bone marrow involves the rearrangement of
immunoglobulin genes.
This leads to the expression in the cell surface membrane of a B cell
receptor (BCR) comprised of an immunoglobulin molecule with two
closely associated transmembrane molecules known as Igα and Igβ 3

4. Development of B lymphocytes
Immature B cell- only IgM on surface.
Negative selection- Self reactive immature B cells are inactivated by
deletion (apoptosis) or anergy (mature but do not respond to
subsequent antigen exposure)
Receptor editing- a change in the Ig specificity of an autoreactive B cell 4

5. Development of B lymphocytes
Mature B cell (naïve B cell) - IgD and IgM on surface.
When activated by exposure to antigen they differentiate into plasma cells and
memory B cells 5

6. Development of B lymphocytes
Some activated B cells differentiate into plasma cells or memory cells
Plasma cells:
Become highly specialized toward antibody secretion.
No longer express surface Ig or MHC class II and therefore are unresponsive to antigen or T cells.
Have a life span of about 4 weeks.
Memory B cells – B cells that persist for a long period of time.
Are generated after proven successful antigen specificities have been produced.
Are much more easily activated on encounter with antigen.
Allow a much quicker and stronger response to antigen than in the primary response. 6

7. B cell membrane proteins needed for signal transduction in the synthesis of antibody after antigenic stimulation 7

8. Development of T Lymphocytes

9. Development of T Lymphocytes
Differentiation of T cells involves the generation of the T cell receptor
(TCR) and is designed to accomplish:
1) MHC restriction
2) Acquisition of self-tolerance.
MHC restriction is the development of mature T cells that recognize
antigen only when it is presented by MHC molecules on the surface of an
APC.
Acquisition of tolerance is the development of mature T cells that do not
respond to self components (i.e. antigens such as proteins, nucleic acids,
and lipids that are normal components of our cells). 9

10. Development of T Lymphocytes
To be of use in an immune response a person's T cells must be able
to interact with ligands formed from peptides bound to self-MHC.
Screening of T cells for the ability to interact with self-MHC takes
place in the thymus.
TCR
MHC I
MHC II 10

11. Development of T Lymphocytes
TCR
MHC I
MHC II
Self Antigen
T cells that emerge from the thymus must not interact with self-MHC presenting self-peptides –peptides derived from constituents of a person's own body.
Mature T cells leaving the thymus are tolerant of self-antigen but responsive to foreign antigens presented by self-MHC. 11

12. Development of T Lymphocytes
During early development, immature T
cells carry 2 co-receptors, CD4 and
CD8 (double positive)
As they mature they lose one to
become CD4+ or CD8+ (single
positive)
The co-receptors serve as adhesion
molecules and signal transducers 12

13. Lymphocyte trafficking and residency in lymphoid tissue
Different lymphocytes, preferentially enter different tissues, in a process
called homing
Mature single positive CD4 or CD8 T cells leave the thymus and enter
the circulation and the secondary lymphoid organs
Most T cell responses to
antigens occur in the secondary
lymphoid organs

14. Lymphocyte trafficking and residency in lymphoid tissue
After TCR recognition of a specific antigen, T cells proliferate into a
population of:
1) Activated T cells
2) Memory cells

15. T-cell Immunity 15

16. Activation of Naive T cells on Encounter With Antigen
T-cell activation (T-cell priming)–the stimulation of a T cell to differentiate into an effector T cell after encounter with antigen.
3 types of effector T cells:
CD8 T cells (cytotoxic T cells)– Migrate to the site of infection. Kill cells infected with viruses or other intracellular pathogens
CD4 T cells (helper T cells) of two types–express CD4 on their surface
TH1 cells– Migrate to the site of infection. Secrete cytokines at site of infection that activate macrophages
TH2 cells– Stay in secondary lymphoid organs. Secrete cytokines in secondary lymphoid organs that primarily help B cells make Igs
Once activated, effector T cells interact with specific antigen presented by target cells. 16

17. TH1 and TH2 cells
Most immune responses involve contributions from both TH1 and TH2 cells.
Cytokines secreted by TH1 cells are biased toward a cell mediated immune response dominated by:
Macrophage activation which leads to inflammation
Cytotoxic (CD8) T cell activity
Cytokines secreted by TH2 cells are biased toward a humoral immune response dominated by B cell differentiation and the production of antibodies (Igs). 17

18. TH1 and TH2 cells
Many antigens give rise to TH1 and TH2 cells, but some antigens
produce more of one than the other
Viruses and bacteria favor the production of TH1 cells
Allergens and parasites favor TH2 induction

19. Activation of Naive T cells on Encounter With Antigen19

20. Dendritic cells carry antigens from sites of infection to secondary lymphoid tissues
The body brings pathogens to secondary lymphoid organs where lymphocytes are activated. Two ways pathogens are carried to the secondary lymphoid organs:
In lymph.
By dendritic cells (DCs) that pick up and process antigens and then migrate to the secondary lymphoid organs.

21. Dendritic cells (DCs) differentiate as they move from a peripheral site of infection to secondary lymphoid tissues.
Mature DCs or activated DCs
Immature DCs. 21

22. Dendritic cells carry antigens from sites of infection to secondary lymphoid tissues
During most passages through the secondary lymphoid tissue the T cell does not find its specific antigen but it can continue to circulate for many years as a small non-dividing T cell.
Once a T cells is trapped in the secondary lymphoid tissue and activated, it takes several days to proliferate and differentiate. This accounts for the time delay between infection and the production of an effective adaptive immune response during the primary immune response.
Most effector T cells leave the secondary lymphoid tissues through efferent lymphatics and rapidly reach the site of infection. 22

23. Activation of naive T cells requires a co-stimulatory signal delivered by a professional antigen presenting cell.
The interaction between TCR and specific MHC : peptide is not sufficient to trigger activation, a co-stimulatory signal from the APC is required. (The co-stimulatory signal must come from the same cell that presents the antigen.)
CD28 receptor on T cell
B7 ligand on dendritic cell 23

24. Activation of naive T cells requires a co-stimulatory signal delivered by a professional antigen presenting cell.
Professional APCs are distinguished from other cells by the presence of the co-stimulatory molecule B7 on their surface.
B7 on the professional APC binds to the receptor protein CD28 on the surface of the T cell.
Binding of the TCR and CD4 or CD8 to the peptide:MHC induces clonal expansion and differentiation only if a co-stimulatory signal is given. 24

25. Professional Antigen Presenting Cells (APCs)

26. Macrophages
Macrophages are specialized to present antigens from extracellular replicating organisms such as bacteria.
Receptors for specific carbohydrate structures unique to bacterial cells are present on the surface of the macrophage.
As a consequence of interactions with microbes through these receptors, macrophages are stimulated to express the co-stimulatory molecule B7 and MHC class II. 26

27. Dendritic Cells
DCs are responsible for initiating T cell responses against viruses.
Immature DCs are highly phagocytic but have no co-stimulatory activity.
When these DCs phagocytize antigens they are stimulated to migrate to secondary lymphoid tissues where they will mature.
Once DCs arrive at secondary lymphoid tissues, they:
Mature.
Lose their phagocytic ability.
Express high levels of :
MHC
Co-stimulatory molecules
Adhesion molecules
Cytokines including some that attract naive T cells 27

28. Dendritic Cells
This process ensures that DCs present only antigens acquired at sites of infection, but don't activate naive T cells until they reach the secondary lymphoid tissue.
Immature dendritic cells are present in epithelial tissues that confront the external environment including the skin, gut, and respiratory tract.
Langerhans' cells–immature DCs of the skin, once these cells reach secondary lymphoid tissue they mature into antigen presenting (interdigitating reticular cells). 28

29. B cells
B cells bind soluble protein antigen from the extracellular environment by means of surface Ig.
Receptor mediated endocytosis causes selective uptake of the protein antigen that is processed into peptides that bind MHC class II molecules. (In this case the surface Ig is the receptor.) 29

30. Professional APCs require stimulation from microbial components for induction of B7 co-stimulatory activity
Professional antigen presenting cells do not express the co-stimulatory molecule B7 unless stimulated by adjuvants –microbial components such as lipopolysaccharide (LPS) that stimulate expression of co-stimulatory molecules.
Because B7 expression needs to be induced, professional antigen presenting cells only activate naive T cells to respond to soluble antigen in the context of an infection, providing one of many mechanisms help prevent immune responses to self antigens.
This explains why vaccines that include whole organisms are much more effective at stimulating an immune response than highly purified antigenic molecules. 30

31. Professional APCs require stimulation from microbial components for induction of B7 co-stimulatory activity 31

32. When T cells are activated by antigen, signals from TCRs and co-receptors alter the pattern of gene transcription.
T cell binding of MHC:peptide and B7 induces the expression or activation of transcription factors. These transcription factors facilitate expression of the genes that cause the changes associated with T cell activation.
When a T cell binds MHC:peptide:
The TCRs, the co-receptors and the MHC:peptide they bind on the opposing cell cluster together.
Receptor clustering initiates a signal that in combination with signals from the co-receptors and co-stimulatory molecules will change the pattern of gene expression: leading to proliferation and differentiation 32

34. Proliferation and differentiation of activated T cells are driven by the cytokine interleukin-2.
Activation of T lymphocytes by professional APCs starts a program of differentiation resulting in:
A burst of cell division.
Acquisition of effector function.
This differentiation program is under the control of a cytokine called interleukin-2 (IL-2), which is produced by the activated T cell. 34

35. Proliferation and differentiation of activated T cells are driven by the cytokine interleukin-2.
The binding of IL-2 to the IL-2 receptor triggers rapid cell division that produces many antigen specific effector T cells from rare antigen specific naive T cells.
The importance of IL-2 in the adaptive immune response is so important that many immunosuppressive drugs used to prevent transplant rejection are designed to interfere with signaling through the IL-2 receptor. 35

36. Antigen recognition by a naive T cell in the absence of co-stimulation leads to the T cell becoming non-responsive.
Naive T cells that bind specific MHC:peptide but don't receive a co-stimulatory signal are unable to make IL-2. They are therefore unable to stimulate their own proliferation and differentiation. 36