1. Development of B and T lymphocytes
Modified from “Serotonin” file
Development of B and T lymphocytes
Ali Al Khader, MD
Faculty of Medicine
Al-Balqa’ Applied University

2. What will we discuss today?
B-cell development
T-cell development

3. B- cell development…overview
Stem cell
In periphery
Pro-B cell
Pre-B cell
Memory B cell
Immature B cell
Mature B cell
Plasma cell
In bone marrow
Modified from “Immunology for medical students, 2nd edition”

4. B- cell development Stem cells… - in fetal liver
- in bone marrow soon after birth
In bone marrow…radial maturation pathway
B lineage cells develop into immature B cells with membrane-bound IgM molecules…these will leave the bone marrow
These will acquire the ability to recirculate and populate all peripheral lymphoid organs
Further maturation primarily in the spleen into follicular B cells expressing IgM & IgD on their surface

5. B- cell development, cont’d
From lymphoid progenitor to mature B cells: 2-3 days
The earliest committed B-lineage cell is pro-B cell
-RAG proteins are first expressed at this stage
-DJ & V to DJ recombination then occurs, and mu heavy chain is
produced
-TdT is most abundantly expressed here
Characterized by appearance of B lineage surface markers, e.g., CD19

6. B- cell development, cont’d
Remember that similar presence of retained segments is important when we will talk about receptor editing of the light chain

7. B- cell development, cont’d
Rearrangements at IgH locus must be productive…1/3 of pro-B cells
…now Ig mu heavy chain can be formed
now the cell becomes: pre-B cell
In early pre-B stage: two polypeptides associate non-covalently to form the surrogate light chain, and pair with the heavy chain
-delta 5
-VpreB

8. B- cell development, cont’d
Surrogate light chains are invariant
Mu + surrogate light chains + Ig alpha + Ig beta = pre-B cell receptor
Bruton’s tyrosine kinase (BTK gene) is activated downstream
Its signaling is responsible for B lineage expansion (survival, proliferation and maturation)
Its mutation will cause: …….

9. B- cell development, cont’d
Pre-B cell receptor also inhibits rearrangement of heavy chain locus on the other chromosome
If the rearrangement was non-productive, the other allele can compensate
Pre-B cell receptor also inactivates surrogate light chain gene expression
Rearrangement of kappa or lambda which associates with mu…here the cell becomes immature B cell

10. B- cell development, cont’d
Kappa is rearranged after heavy chain and before lambda
…rearrangement of kappa inhibits lambda rearrangement
…2 conditions in which lambda will undergo recombination???
Allelic exclusion also applies for light chain
Immature B cell will exit the bone marrow and complete maturation in spleen
…otherwise they -undergo receptor editing
-die
-or become unresponsive
By reactivation of Rag genes and new recombination of light chains
(Negative selection)
= clonal deletion
= anergy

11. B- cell development, cont’d
Mature naive B cells will die in a few months if they do not encounter antigens and recognize them with high affinity (respond to antigens)
For mature B cells expressing IgM & IgD: binding with high affinity leads to proliferation & differentiation…leads to humoral immune responses
B-1 and marginal zone B lymphocytes?????

12. T- cell development…overview
Positive selection if recognize self MHC and negative selection if recognize self MHC with self-peptide antigens
Double-negative (CD4- & CD8-)…in subcapsular zone
Commitment to alpha beta or gamma delta lineage
Double-positive cells…in cortex
Selection of DP cells by MHC class I or class II molecules…in cortex
Selection of single-positive cells depending on the MHC molecule….in medulla
Release of naive mature T cells
So those that are self-tolerant and self-restricted are retained
= lineage commitment

13. T- cell development
Congenital absence of thymus will cause immunodeficiency
Thymus involutes with age…but memory T cells have long life span
Precursors from fetal liver and adult bone marrow will seed the thymus
… thymocytes

14. The TCR 2 lineages …95% alpha beta …the remainder: gamma delta
Ch. 14
Ch. 7
2 lineages …95% alpha beta
…the remainder: gamma delta
Accessory molecules for TCR: -CD3 (4 transmembrane protein
chains…gamma, delta, epsilon and zeta)
-LFA-1 (= CD11a)…an integrin
within
Ch. 7
transmembrane
*Beta & delta: VDJ
*Alpha & gamma: VJ
*A tyrosine kinase (Lck…of Src family) is brought into proximity of CD3 cytoplasmic part…by CD4/CD8

15. T- cell development, cont’d
The most immature thymocytes: negative for TCR, CD4 or CD8
In cortex: expression of gamma delta and alpha beta TCRs…see next slide
Alpha beta T cells begin to mature into CD4+ class II MHC-restricted or CD8+ class I MHC-restricted T cells…see slide 17
Then to the medulla then to the circulation
Role of other cells in thymus (expressing MHC & secreting cytokines)
In subcapsular sinus and outer cortex
(+) for CD44 & CD25 (alpha chain of IL-2 receptor)

16. T- cell development, cont’d
Cortical thymocytes… proliferation and apoptotic activity
Rearrangement of beta, gamma, and delta
-at DN stage
-if functional gamma delta receptor produced…gamma delta TCR-expressing T cell results
-if TCR beta chain…with invariant pre-T alpha chain and CD3: = pre-TCR complex…signal transduction:
stimulation of proliferation, halting beta rearrangement and promoting alpha rearrangement
95% before reaching the medulla
Sensitive to irradiation and steroids

17. T- cell development, cont’d
Positive selection of DP thymocyte…with help of cortical epithelial
cells
Self-MHC restricted cells are produced
…these need to be self-tolerant…otherwise??
With help of dendritic cells in medulla

18. Autoimmune regulator gene (AIRE)
Regulate expression of antigens of endocrine cells in thymic epithelial and non-epithelial cells
Mutation…autosomal recessive disease autoimmune polyendocrine syndrome I (APS-I)

19. Thank You