what is the effect of negative IL-7 signals on: 1. pre-BCR & IL-7 signals 2. RAG 1/2 3. light chain VLJL rearrangement 4. proliferation

1. decrease pre-BCR and IL-7 signals 2. increase RAG 1/2 3. increase light chain VLJL rearrangement 4. decrease proliferation

Lectures 22 & 23 B and T Cell Development Flashcards by Alexa Crawford

hematapoietic stem cells (HSC) divide and the progeny become ____ cells in the bone marrow

common lymphoid progenitor

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in what stages of life does the transformation of hematapoietic stem cells to common lymphoid progenitor cells occur?

begins in fetal life and continues throughout life

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common lymphoid progenitor cells that are destined to become B cells acquire ___ on their surface

B220 (CD45R)

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once B cells have successfully rearranged their BCR (Ig_), where do the cells travel to?

IgM; travel to periphery where they mature in the spleen and then circulate as mature naive B cells between blood and lymph nodes

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what recombination occurs in progenitor B cells?

DJH chain recombination and start of V-DJ-H recombination

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what recombination occurs in pro-B cells?

V-DJ-H chain recombination

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in what stage of B cell development is u H chain expressed as the pre-BCR?

precursor Pre-B cells

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what type of recombination occurs in the precursor pre-B cells?

VJL chain recombination

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in the pre-B stage, the cells undergo several rounds of ____

cell division

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in what stage of B cell development are mIgM expressed?

immature B cells

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in what stage of B cell development does negative selection start?

immature B cells

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what type of negative selection are immature B cells capable of?

deletion & receptor editing

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in B cell development, what is the effect of positive IL-7 signals on 1. survival & proliferation, 2. RAG 1/2 3. Vh-DJh rearrangement (HC allelic exclusion)?

promotes survival & proliferation
decrease RAG 1/2
decrease VH-DJh rearrangement

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what is the effect of negative IL-7 signals on:

pre-BCR & IL-7 signals
RAG 1/2
light chain VLJL rearrangement
proliferation

decrease pre-BCR and IL-7 signals
increase RAG 1/2
increase light chain VLJL rearrangement
decrease proliferation

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pre-BCR made up of u heavy chain & surrogate light chains inhibits ___ rearrangement and induces ___ rearrangement

u; k

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u & k in the pre-BCR inhibit rearrangement of ___allele and ___ rearrangement

K and lambda

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in what part of the body does negative selection first occur?

bone marrow

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t/f many B cells die in the bone marrow due to negative selection

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what is central tolerance?

loss of B cells with self-reactive autoantibodies form the bone marrow

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how does central tolerance of B cells occur?

clonal deletion of autoreactive B cells

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what is clonal deletion?

induced apoptosis of IgM+ immature B cells with self-reactive BCR while still in the bone marrow

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autoreactive B cells that are not caught by clonal deletion, can undergo ____ editing

light chain receptor editing

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what segments get rearrange in light chain receptor editing?

the remaining V and J segments on the same chromosome

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some autoreactive B cells that escape clonal deletion become ___ due to exposure to self-antigen or become unresponsive to antigen, these cells are called ___ and are short-lived

anergic; transitional T3

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in light chain rearrangement, the first rearrangement btwn __ and __ regions is productive, but the combination of teh resultant light chain with Ab results in an ____ antibody

V3 and J3; autoimmune

in light chain receptor editing, the second rearrangement btwn __ and __ is productive and the combination with Ab heavy chain results in an _____ antibody

V2 and V4; nonautoimmune antibody

does the transition from immature to mature B cells occur outside the bone marrow?

yes

T1 B cells migrate to the ___ where a second round of ___ and further maturation occurs

spleen; negative selection

self reactive T1 cells are eliminated by ___

negative selection

the maturation of T1 B cells to T2 B cells is done by ____ selection

positive

T2 B cells mature to ___ cells, the largest pool of B cells

B-2

the transition of T2 B cells to B-2 cells is dependent on stimulation through ____

BAFF receptor

B-2 cells circulate for ~____ months

4.5

B-1, B-2, and marginal zone B cells all express __ and ___ immunoglobulins

IgD and IgM

during B cell development, the BCR signals through ____ and ___

Ig alpga and Ig beta

the BCR iga/igB have ____ motifs which can become phosphorylated

immunoreceptr tyrosine-based activation motifs (ITAM)

cross linking the BCR brings ___ into close proximity and they will phosphorylate the ITAMs

src family tyrosine kinases

phosphorylated ITAMS of BCR become docking sites for ____ and once it docks and becomes activated it causes multiple signalling events

syk kinase

what is the requirement for T-dependent B cells development?

contact with T cells through CD40 (using CD40L) to co-stimulate

are memory B cells made as a result of T-dependent or T-independent development?

T-depenent

cytokines modify the response of T-dependent or T-independent B cell development?

T-dependent

what causes B cell activation in T-independent (TI-1) B cell development?

polyclonal activators like some bacteria

what causes T independent (TI-2) B cell development?

highly repetitious molecules (like polymeric proteins, cell wall polysaccharides which cross link BCR with CD21

what are 3 proliferation cytokines that cause activated B cells to proliferate?

IL-2, IL-4, IL-5

what cytokines cause proliferating B cells to differentiate into specific types of B cells?

IL-2, IL-4, IL-5, IFN-y and TGF-B

IFN-y causes proliferating B cells to differentiate into ____ cells

plasma

which B cells secrete IgG2a or IgG3?

plasma cells

TGF-B causes proliferating cells to differentiate into plasma cells that produce what Ig?

IgA or IgG2b

IL-4 causes proliferating B cells to differentiate into plasma cells that secrete what type of Ig?

IgE or IgG1

IL-2, IL-4, and IL-5 cause proliferating B cells to differentiate into plasma cells that secrete what Ig?

IgM

T cell development occurs in what gland?

thymus

the thymus has well-defined ___ and ___ regions

cortical and medullary regions

t/f the thymus is richly innervated

what is the effect of stress on cortical thymocytes?

rapid loss, thought to be at least pertly bc of the effect of steroids such as glucocorticoids

what happens to the size of the thymus during pregnancy and old age?

gets smaller (involutes)

in older people, the involution of the thymus is associated with decreased function of ___ cells

hematopoietic stem cells are attracted to the thymus from the bone marrow by ____

chemokines

development of T cells in the thymus is dependent on the ___ being secreted from thymic epithelial cells and it binding to the receptor ___ on the lymphocyte

notch ligand; notch

while T cells are developing in the thymus, they are called ____

thymocytes

the maturation process of T cells takes between __ and __ weeks

1 and 3

a prothymocyte enters the thymic cortex where ___ and ___ are expressed

Thy-1 and TDT

when pre-T cells are in the stage of rearranging their TCR genes, they are called ___ or ___ cells

CD3+CD4-CD8- or double negative T cells

double negative T cells that successfully rearrange their gamma & delta chain gene segments develop into the ____T cells that are exported to the periphery in small numbers

CD3+CD4-CD8- gamma/delta T cells

what is allelic exclusion in T cell development

successful rearrangement of a set of TCR genes supresses further rearrangement of TCR genes on the second chromosome

what is odd about the alpha chain of the TCR?

alpha V region proximal regions recombine first (3-5 cycles of V-J rearrangements per cell)

t/f the majority of double-negative cells will go on to rearrange beta and alpha chain gene segments

t/f gamma delta T cells with TCR that are encoded by specific V-gamma-gene segments are exported from the thymus at defined periods of fetal and newborn development and then migrate to populate epithelial rich tissue in adults

the delta gene segments of the TCR are nested between ___ gene segments

alpha

once a T cell rearranges its alpha segments of the TCR, the ___ segments will be lost

delta

double positive T cells can undergo selection for reactivity to self to ensure what 2 things?

1. self-tolerance | 2. MHC restriction

positive and negative selection of T cells in the cortex of the cotex of the thymus involves a ___ interaction between immature thymocytes and cells in the cortex

physical

if the thymocytes bind too strongly to self cortex cells, what happens to them?

die by clonal deletion (neagtive selection)

if thymocytes do not interact at all with the cortex epithelial cells, what happens to them?

death by neglect

only thymocytes with what level of affinity for self-MHC on cortical thymic epithelial cells survive

low/intermediate (positove selection)

thymocytes that are positively selected, upregulate ___ and migrate to the medulla

CCR7

when thymocytes are positively selected, they become ___ or ___ cells

CD4 or CD8 single positive cells

what are the 3 proposed models of lineage commitment in T cells?

1. instructive model 2. stochastic model 3. kinetic signalling model

what is the instructive model of T cell lineage commitment?

assumes multiple interactions between the TCR, CD4 or CD8 co-receptors and MHC instruct T cells to differentiate

what is the stochastic model of T cell lineage commitment?

suggests that one co-receptor is shut off randomly, independently of interactions with the TCR

what is the kinetic signalling model of T cell lineage commitment?

all cells show reduced CD8, so stronger positive selecting TCR results in CD4 but an interrupted TCR signal with IL-7 leads to CD8

in negative selection of thymocytes in the medulla, there is a physical interaction between ____cells and the thymocytes

dendritic cells and macrophages

what happens to thymocytes in the medulla if they have high affinity TCR for self MHC/self-antigen?

die by apoptosis

thymocytes that make it through the cortex and medulla are released into the peripheray as ____, which require further maturation to naive T cells which is thought to be from further ___ interactions

recent thymic emigrants; MHC

small populations of double positive T cells can become other cell types such a:

NKT cells, T reg cells and intraepithelial lymphocytes (IEL)

while strong interactions between TCR and CD4 or CD8 in the thymus leads to ____, this strong interaction in teh periphery lead to ____

cell death; proliferation

stimulation of T cells through the TCR is done in collaboration with ___

CD3

what is the function of CD45 in TCR signalling?

CD45 is a tyrosine kinase that removes an inhibitory phosphate, activating the src kinase Lck

Lck is associate with ___ and ____

CD4 and Cd8

what is the function of Lck in TCR signalling?

phosphorylates the ITAMs on CD3 to which ZAP-70 docks

what is the function of ZAP-70 in TCR signalling?

becomes phosphorylated and activated by lck then catalyses other phosphorylations that lead to gene expression, differentiation and activation

what are hematapoietic stem cells?

stem cells that can differentiate into any type of WBC in the blood or tissues

what are 3 types of lymphocytes?

mostly b and T cells, but can also have innate lymphoid cells

what is a CLP?

common lymphoid progenitor

why are RAG1/2 downregulated once a B cell has successfully rearranged its mu heavy chain?

if there was too much RAG1/2, the second allele may try to rearrange and that would cause issues

can B cells express more than 1 heavy chain?

increased RAG 1 & 2 results in more ____ chain rearrangement

light

will light chain receptor editing happen if there are no other J regions?

the ____ regions of IgM and IgD are identical and the ____ regions are different from each other

light chain/ variable region; constant

can class switch occur in TI-1 or TI-2?

no, so they will only secrete IgM

the Thy-1 in T cells is thought to be equivalent to the ___ of B cells

B220

when babies are in-utero, they have ___ Tcells and after birth they are replaced by ____ T cells

delta gamma; alpha beta