Chapter 8: Development of B and T Lymphocytes Flashcards
What are B lymphocytes derived from?
- Hematopoietic stem cells give rise to B, T, or innate lymphoid cells
- Regulation via network of transcription factors
What are two major cell groups in bone marrow?
Hematopoietic cells
- Immature blood cells
Stromal cells
- Supporting cells help hematopoiesis through soluble and membrane bound cytokines
- Adipocytes, mature blood cells, cells involved in bone remodeling
How is the progress of gene rearrangement monitored?
- Progress is monitored through production of a protein chain
- Serves as signal for cell to progress to next stage
- Only successful arrangements produce protein chain
- Determination of B or T cell dependent of transcription factor network
What does early B cell development depend on? How is development initiated?
- Dependent on bone marrow stromal cells
- Intiated by activation of transcription factor E2A
How does B cell development occur?
- Begins by rearrangement of heavy chain locus
- Initiated in pro-B cell when E2A and EBF induce expressions of proteins (RAG-1,-2)
What rearrangement occurs in Early pro-B cell development? Late pro B?
- First rearrangement is joining D gene to J segment at immunoglobulin heavy chain locus
- V to DJ arrangement
- successful rearrangement leads to production of intact heavy chain required for pre-B receptor
- Produces surrogate light chains
- Pro B that do not produce chains are eliminated
- 45% of pro-B cells are lost
What is a large pre-B cell? Small pre-B cell?
- Express pre-B receptor
- Contains surrogate light chains
- Signaling promotes heavy chain-allelic exclusion
- Prevents heavy chain rearrangement stimulates proliferation if bound IL-17
- Rearrangement of light chain locus
- RAG proteins are produced again
What is an immature B cell?
- Fully assembled BCR (IgM)
- Allelic exclusion and isotypic exclusion
- Cells that don’t produce fully functional BCR are eliminated (2nd checkpoint)
What happens before B cells leave the bone marrow? What happens if is strongly reactive?
- Tested for autoreactivity (central tolerance)
- If strongly reactive, cell development is arrested and cell undergoes receptor editing
- Some weakly reactive B cells will be kept. Some autoimmunity is always present
What happens if after receptor editing, a receptor is still auto reactive?
- Self reaction leads to expression of recomb. protein RAG
- Light chain is replaced until non reactive receptor is produced or no segments available to recombine
- **If new receptor is still autoreactive, it undergoes apoptosis (clonal deletion)
- Defects contribute to rheumitoid arthritis and lupis
What is a transitional B cell? What happens to most transitional B cells
- Immature B cells that exit the bone marrow to spleen to continue final steps of maturation. Undergo peripheral tolerance
- Most transitional B cells die due to competition for access to follicles in spleen. Follicles provide cytokines necessary for B-cell survival and maturation
- Follicles favor entry of mature B cells
What are the two stages before reaching a naive B cell? WHat happens after the transitional stage?
- T1 is when low levels of IgD and high IgM
- T2 is when ther is increased levels of IgD
- Maturity defined by presence of B cell coreceptor CD21
- B cells enter long lived peripheral pool as follicular B cell (B-2) or marginal zone B cell
- Divergence at T2 stage, BCR specificity determines type of B cell
What is a B-1 B cell? What does it recognize? How is it generated? What is an FO and MZ B cell?
- Major producer of natural antibodies
- Does not require T cells
- Antibodies recognize capsular polysaccharide antigens
- Generated by progenitor cells in fetal liver
How and where do precursors commit to the T cell lineage? How are T cells developed and distributed across the body?
- Precusors commit to T cell lineage after Notch signaling in thymus, initiate TCR gene rearrangement
- T cell progenitors develop in bone marrow then sent to thymus to complete development. Then mature T cells migrate to peripheral lymphoid organs and activated T cells migrate to sites of infection
Describe how T cells develop in the thymus.
- Thymocytes originate from bone marrow
- Cortex consists of mostly thymocytes and a few macrophages
- Medulla consists of more mature thymocytes, a few B cells, macrophages, dendritic cells
- Thymic epithelial cells (TEC) plays a major role in T cell development
Why do 98% of thymocytes die from apoptosis?
- Intensive screening for the ability to recognize self peptide: Self MHC complexes and for self tolerance
Describe the development of T cells in terms of expression of TCR and cell-surface proteins.
- Thymocyte will initially be negative for CD3,4,8
- Thymocyte can then become either CD3+ or CD3,4,8 large (double positive)+
- CD3+ sent to periphery
- CD3,4,8 large positive becomes small resting (double positive)
- Will then become either CD4+ or CD8+
- Exported to periphery
What do early thymic progenitors(ETP) do?
- Also known as DN1 arrive to thymus from bone marrow
- Express SCF receptor Kit
- Receive signal from TECs that is transduced by notch receptor
- Initiate T cell specific gene expression and commitment to T cell lineage
- TCF1 + GATA3 express genes encoding component of CD3 and RAG proteins
- IL-7 receptor expression
- Notch signaling continuity is important
What happens to Pro-T (DN2)?
- Express CD25
- Reduction in Kit expression
- Cells become more committed to T lineage
- BclllB TF
- TCR beta chain gene rearrangement begins
- D and J rearrangement
What happens to small pre-T (DN3)?
- Fully committed
- Lost Kit expression
- TCR beta chain rearrangement complete
- Expression of beta chain
-
Express invariant chain pTalpha and CD3 to form pre-TCR
- Signaling doesnt require ligand
- Allelic exclusion
- Proliferation
What happens to large pre-T (DN4)?
- Loss of CD25
- Expression of coreceptors CD4 + CD8 begin
- Rapid cell proliferation into double positive cells
What is a double positive or single positive T lymphocyte?
Double positive
- Majority of thymocytes
- Express CD4 and CD8
- Alpha chain locus rearrangement
- Expression of TCR
- Cells begin to undergo positive selection
Single positive
- Express one of the coreceptors
- Undergo negative selection
What order does T cell development follow?
ETP-> DN2-> DN3-> DN4-> DP-> SP
Where in the thymus do the different stages of T cell development occur?
- DN1 enters thymus from blood stream via venules near cortico-medullary junction
- Ligands that interact with Notch receptor and on immigrant cells
- Medulla contains mature single positive T cells which eventually leave the thymus
What is positive selection? What is negative selection?
Positive:
- T cells must be able to recognize self-MHC molecules
- Failure results in apoptosis
- Determination of CD4 or CD8 lineage and transcriptual programming
- Mediated by cortical epithelial cells
Negative:
- T cells that react strongly to Self-MHC or self-MHC + antigen complex = elimination
- Mediated by antigen presenting cells and medullary epithelial cells
Describe positive selection.
- TCR recognizing peptides: MHC II complexes receive strong and persistent signaling leading to upregulation of TF ThPOK
- ThPOK induces maturation of CD4 and promotes expression of Helper t cell genes
- TCR recognizing peptide: MHC I complex receives weaker signaling and w/ cytokines induces expression of TF Runx3
- **Runx3 induces the maturation of CD8 and promotes expression of cytotoxic genes
What happens if a T cell alp[ha chain is not positively selected?
- T cell alpha genes undergo successive rearrangements until positive selection or cell death
Describe what happens in negative selection.
- Occurs in the thymus and continues to periphery
- Purges T cells with self reactive receptors
- ** Medullary epithelial cells express tissue-specific proteins found outside of thymus present in T cells
- Controlled by AIRE
- APC presents self antigens obtained by other cells or their environment
- The signals a T cell receives during inflammation prevents T cell from undergoing apoptosis when it binds to a foreign antigen
