T/B-cell Development Flashcards
What is the origin of B and T cell lineages?
Multipotent HSC
= differentiates into CLP (common lymphoid progenitor)
= gives rise to B cells, T cells and ILCs (via Pro-B or T cell, ILC precursor)
= T cell, ILC precursor that express the transcription factor: Notch1 and GATA3 become pro-T cells
= T cell, ILC precursors that express the transcription factor: Id2 become ILCs
= CLP that expresses: EBF, E2A and Pax5 = become Pro-B cells
What are the types of T cells?
T cells
= defined by possession of a T-cell receptor (TCR)
Overall purpose of T-cell development
= production of T cells that interact with MHC (for antigen presentation)
= BUT do not respond to self-antigens
Three main types of mature naive T cells produced in the thymus
= αβ CD4+ T cells (helper T cell precursor)
= αβ CD8+ T cells (cytotoxic T cell precursor)
= δγ T cells
What are the stages of T-cell development?
Early stages = TCR independent
= commitment to the T cell lineage
= initiation of TCR gene rearrangements
= selection + expansion of cells that have successfully rearranged their β TCR genes (= β-selection)
Late stages = TCR dependent
= positive selection for self-MHC recognition (TCR binding = survival)
= negative selection for self-antigens (TCR binding = death)
= commitment to CD4+ OR CD8+ lineages
What happens in the Stem cells to DN thymocytes part of T cell development?
= uncommitted CLP enters the thymus from the bone marrow
(capable of developing into several cell types: B cells, ILCs, NK cells …)
= those that express receptor: Notch = become T cells
(interact with Notch ligands expressed by cells in thymus = become committed to T-cell lineage)
= immature T cells (thymocytes) sub-divided by expression of co-receptor CD4 or CD8
(at first they express neither = double negative (DN) thymocytes)
= they progress through four stages of development (DN1-DN4)
= during DN1-DN4 = they proliferate and rearrange the TCRβ, δ and γ antigen receptor genes
What happens in the DN to DP thymocytes stage of T cell development?
= thymocytes that rearrange δ and γ receptor genes successfully mature to the TCRγδ lineage
= thymocytes that successfully rearrange the β receptor chain are detected by process called = β-selection
= β-selection initiated by assembly of the TCRβ protein with a surrogate, invariant TCRα chain and CD3 complex proteins
= pre-TCR assembly results in commitment to the TCRαβ lineage, another burst of proliferation to the double positive (DP) stage of development + initiation of TCRα rearrangement
What happens from DP thymocytes onwards in T cell development?
= DP thymocytes are most abundant in subpopulation of thymus
(are the first cells to express a mature TCRαβ receptor)
= are targets of positive selection (responsible for self-MHC restriction) and negative selection (responsible for self-tolerance)
= positive and negative selection regulated by affinity of TCR on a DP thymocyte for MHC/self-peptide complexes expressed by the thymic epithelium
= high-affinity TCR/pMHC interactions result in negative selection
(typically by initiating apoptosis - clonal deletion)
= low/intermediate-affinity signals result in positive selection
(initiate a maturation programme to the helper CD4+ or cytotoxic CD8+ single-positive lineages)
= large majority of thymocytes (95%) do not interact with any MHC / self-peptides expressed by thymic epithelium
(die by neglect)
What happens in the lineage commitment stage of T cell development?
= positively selected DP thymocytes undergo lineage commitment to become: helper CD4+ or cytotoxic CD8+ T cells
= thymocytes whose TCR preferentially interacts with MHC class II generate a continuous signal that initiates CD4+ helper T cell developmental programme
= thymocytes whose TCR preferentially interacts with MHC class I cannot generate a continuous signal
(because CD8 surface levels are down-regulated in response to positive selection)
= interruption in signalling followed by further stimulation = initiates CD8 developmental programme
= in cortex, DP thymocytes browse MHC I or II displaying self peptides
(derived from common intracellular or extracellular proteins on cTECs - cortical thymic epithelial cells)
= those that bind with low/intermediate affinity = progress and mature to SP thymocytes (CD4+ or CD8+)
= in the medulla AIRE+ mTECS display tissue-specific antigens on MHC and mediate negative selection directly or indirectly via dendritic cells
= fully mature thymocytes exit the thymus and undergo final functional maturation in peripheral lymphoid tissues
What other cell types are part of lineage commitment?
DP thymocytes can commit to become other types of lymphocytes:
(signalling cues for alternative development unclear at present)
NKT cells
= natural killer T cells
= express a TCR with an invariant TCRα chain
= interact with CD1 molecules presenting lipid antigens
IELs
= intraepithelial lymphocytes
= usually CD8+, but also have features of innate immunity
Tregs
= regulatory T cells
= control immune response after antigen is cleared from body
= CD4+ subset that helps quench adaptive immunity
What are T regulatory cells?
= some self reactive CD4+ T cells that recognise self antigen in the thymus are not deleted
(BUT differentiate into regulatory cells that are specific for that antigen)
= Tregs that develop in thymus = natural TREG
= they share periphery with Treg that develop from conventional T cells (induced or iTregs) + play important role in inhibiting autoimmune responses
= Tregs express the transcription factor FoxP3
(downregulate T cell function in various ways)
What types of B cells are there?
= B cells defined by possession of a B-cell receptor (BCR)
Major lineages of B cells are
= Follicular (B2) B cells
= B1 B cells
= Marginal Zone B cells
How do B1 cells develop?
= B-1 B cells originate during foetal development where haematopoiesis occurs in the foetal liver
= constitute 30-50% of B cells in pleural and peritoneal cavities of mice
= have a relatively limited receptor repertoire
= receptors tend to bind microbial carbohydrate antigens
(bind with relatively low affinity, much more similar to PRRs of innate immunity)
How do B2 cells develop?
= B cell development begins in bone marrow and is completed in the spleen
= haematopoietic stem cells and developing B cells make contact with various sets of bone marrow cells (stromal cells) as they progress and commit
= immature B cells emerge from bone marrow as transitional 1 (T1) B cells and circulate to the spleen
What happens in B-cell maturation? (B2 cells / Marginal Zone cells)
= T1 B2 cells enter follicles of the spleen
(where level of IgD expression increases)
= they become T2 cells, then mature into either a follicular B2 cell (FO B cell) or a marginal zone (MZ) B cell
= follicular B2 cells can exit the spleen and circulate between and populate secondary lymphoid tissues throughout the body
(mediating the main B cell response to infection)
= MZ B cells remain in the spleen and are specialised for detection of blood-borne antigens
(including protein and carbohydrates, mainly produce IgM)
What is B cell Self-Tolerance?
= B cells must undergo both positive and negative selection
= positive selection = occurs via the ability to form a functional BCR
(developing B cells that cannot form a BCR die)
= immature B cells expressing a BCR specific for self-antigens present in bone marrow are deleted by apoptosis
= no equivalent of the AIRE protein found yet
= interactions with self-antigens in spleen is another chance for negative selection = can give rise to apoptosis
Compare B cell vs T cell development?
Share many characteristics:
= rearrangement of gene segments
= screening processes to avoid self-reactivity
= production of small subsets with discrete function
= production of larger “general purpose” subsets
