B cell Development Flashcards
What cells can arise from common lymphoid progenitors (CLP)
They can give rise to B cell, T cells, or innate lymphoid cells
What is the site of B-cell differentiation?
B-cell development begins in the bone marrow and is completed in the periphery.
What is the entire differentiation of HSC to CTL?
As HSC descendants progress along their chosen lineages, they also progressively lose the capacity to contribute to other cellular lineages. For example, MPPs that are induced to express the 121 receptor Flt-3 lose the ability to become erythrocytes and platelets and are termed lymphoid primed, multipotent progenitors (LMPPs) (Figure 2-3). As LMPPs become further committed to the lymphoid lineage, levels of the stem-cell antigens c-Kit and Sca-1 fall, and the cells begin to express RAG1/2 and TdT, enzymes involved in the generation of lymphocyte receptors. Expression of RAG1/2 defines the cell as an early lymphoid progenitor (ELP). Some ELPs migrate out of the bone marrow to seed the thymus as T-cell progenitors. The rest of the ELPs remain in the bone marrow as B-cell progenitors. Their levels of the interleukin-7 receptor (IL-7R) increase, and the ELP now develops into a CLP, a progenitor that is now c-Kit Sca-1 IL-7R and has lost myeloid potential. However, it still has the potential to mature into any of the lymphocyte lineages: T cell, B cell, or ILC.
Define HSC and stromal cells.
Describe the steps taken for HSC to differentiate into Pre-B cell.
HSC: within the bone marrow, they differentiate into many cell types
Stromal cells: they express proteins (including cell-surface ligands, cytokines, and chemokine) that support the long-term survival and division of HSCs and the developmental pathways leading to the formation of mature blood cells.
HSCs being their life in close contact with osteoblasts in an area near the lining of endosteal (bone marrow) cavity. This endosteal niche, as it is known, provides an environment supportive of long term maintenance of HSCs. HSCs express the receptor c-kit, which binds the ligand stem cell factor (SCF), maintaining the cells in this niche and influencing their differentiation into progenitor cells.
Once it differentiates to the pre-pro-B-cell stage, a developing B cell requires signals from the chemokine CXCL12, secreted by certain stromal cells, in order to progress to the pro-B-cell stage.
Pro-B cells then require signaling from the cytokine interleukin 7, which is secreted by yes another stromal cell subset, to mature to the pre-B stage.
What transcription factors and receptors are expressed by HSCs in becoming common lymphoid progenitor cells?
HSCs express a unique set of surface proteins, some of which play key roles in initiating hematopoiesis.
- Express c-kit (triggers key signals that help to induce differentiation into multi-potent progenitor cells) and sca-1 receptors to receive survival signals from growth factors
- MPPs lose self renewal
- MPPs retain ability to differentiate
- In progenitor cells bound for a lymphoid fate, the transcription factors Ikaros, Purine box factor 1 (PU.1), and E2A participate in the earliest stages of lymphocyte development.
- Ikaros: recruits chromatin-remodeling complexes to DNA and ensure the accessibility of genes necessary for B-cell development
- PU.1: determine lymphoid versus myeloid differentiation, low level factor lymphoid differentiation
- E2A is activated by both above and is critical in B-cell development .
What is expressed on early lymphoid progenitors (ELP) and common lymphoid progenitors (CLP)
As cells become increasingly committed to the lymphoid lineage and start preparing to rearrange their antigen receptor genes, they begin to express RAG 1/2, which defines the cell as an early lymphoid progenitor cell (ELP)
As the levels of the IL-7R increase, expression of c-kit and sca-1 proteins decrease and the ELP develops into a common lymphoid progenitor (CLP)
At the CLP stage, the progenitor on its way to B-cell commitment has lost myeloid potential but still retains the potential to mature along pathways leading to T cells, natural killer cells, and conventional dendritic cells. Signals received through the IL-7R, together with transcription factors E2A and Foxo1, activate expression of the key transcription factor early B-cell factor 1 (EBF1) , which is required for later steps in the B-cell differentiation pathway.
What pathway is used for B-cell developement in the bone marrow?
What are the two systems of nomenclature for B-cell developement?
What is expressed and occurring in pre-pro B cells?
With the acquisition of the B-cell lineage–specific marker B220 (CD45R), and the expression of
increasing levels of the transcription factor EBF1, the developing common lymphoid progenitor
enters the pre-pro-B-cell stage
At the pre-pro-B-cell stage, EBF1, along
with E2A, binds to the immunoglobulin heavy-chain locus, promoting accessibility of the D-J gene
segments and preparing the cells for the first step of Ig gene recombination
What is expressed and occurring in Pro-B cells?
In the early pro-B-cell (progenitor B cell) stage, D-to-J recombination is completed and the cell
begins to prepare for V -to-DJ joining. However, this final heavy-chain recombination event and
the establishment of stable B-lineage commitment awaits the expression of the quintessential Bcell
transcription factor, PAX5, which will then be expressed throughout B-cell development until
the mature B cell is activated by antigen to differentiate into antibody-secreting plasma cells (see
Chapter 11). PAX5 feeds back to reinforce EBF1 expression, thus
generating a powerful feed-forward regulatory loop.
Transcription of genes controlled by the PAX5
transcription factor denotes passage to the late pro-B-cell stage of development, at which point the
expression of non–B-lineage genes is permanently blocked. Like EBF1, PAX5 can also act as a
transcriptional repressor, blocking Notch1 gene expression and thus any residual potential of the
pro-B cell to develop along the T-cell lineage.
What is expressed and occurring in Pre-B cells?
With which type of progenitor are Pre-B cell receptors expressed and what is occurring?
What stages occur after late-pro B cell?
What are immature B cells?
Final step, occurs after small pre-B-cell
What is tolerance induction
Some are lost from the repertoire prior to leaving the bone marrow by the BCR mediated induction of apoptosis, resulting in clonal deletion.
Other auto-reactive B cells reactivate their RAG genes to initiate the process of light-chain receptor editing. The loss of B cells bearing self-reactive receptors within the bone marrow by either of those mechanisms is referred to as central tolerance.
As we will see later, some auto-reactive B cells that recognize soluble self antigens within the bone marrow may survive to escape the bone marrow
environment, but become anergic, or unresponsive, to any further antigenic stimuli.
What are the overall steps in the creation of a mature B cell?
What happens to self-reactive B cells and what evidence did we use?
Are B-cells exported from the bone marrow fully functional?
What types are there and where do they go?
What’s the difference?
What is the difference between T1 and T2 cells? (receptor)
Most T1 B cells differentiate to T2 B cells within the spleen, but a minority (about 25%) of transitional B cells emerge from the bone marrow already in the T2 state.
What are B-2 B cells?
What is expressed other surface?
What is another name?
T2 B Cells Give Rise to Mature Follicular B-2 B Cells
What are T3 B cells?
Recent experiments have suggested that the T3 population may represent transitional B cells that have been rendered
anergic by contact with soluble self antigen in the spleen (and possibly elsewhere) but have not yet been eliminated from the B-cell repertoire.
What are B-1 B cells?
B-1a cells are characterized by their ability to produce natural antibodies, which are antibodies that are produced without prior exposure to a specific antigen. These antibodies are usually low affinity, meaning they have a lower binding strength to the antigen, but they provide rapid protection against a broad range of pathogens. B-1a cells also have the ability to self-renew, meaning they can divide and produce more B-1a cells.
On the other hand, B-1b cells do not have the same self-renewal capacity as B-1a cells, and they do not produce as many natural antibodies. However, B-1b cells have been shown to respond to specific antigens, and they are capable of producing high-affinity antibodies upon antigen stimulation.
In summary, B-1a cells are important for the production of natural antibodies and have self-renewal capacity, while B-1b cells can produce high-affinity antibodies upon antigen stimulation but do not have the same self-renewal capacity as B-1a cells.
- TdT is minimally expressed in the precursors of B-1a cells, thus contemplated (N)-nucleotide diversity is more limited in the antibodies they produce.
- receptors tend to bind microbial carbohydrate and lipid antigens with relatively low affinity
- the receptors are much more similar to the PRRs of innate immunity.
- B-1 B cells secrete antibodies even in the absence of antigen stimulation called natural antibodies
- the antibodies are primarily IgM but may also be IgG or IgA
- t-cell help is not required but does enhance antibody secretion
- These cells undergo apoptosis unless they interact with self-antigen.
What are marginal-zone cells and where are they found?
What characteristics that are shared with B and T cell development? (4)
What are differences between B and T cell development
