Chapter 12
Lymphocytes and the Nervous System
Larisa Y. Poluektova
Questions
1.
Briefly summarize the major steps in lymphocyte embryonic development.
2.
Briefly summarize the major steps in T lymphocyte development.
3.
Briefly summarize the major steps in B lymphocyte development.
4.
Briefly summarize the distribution of B cells and their function.
5.
Briefly summarize the major steps in helper cells polarization.
6.
Briefly describe the development of central tolerance to myelin.
7.
Briefly summarize the major factors that limit T cells survival in the brain.
Multiple Choice
8.
Which of the following cell types exist in thymus?
a. thymic epithelial cells
b. dendritic cells
c. macrophages
d. CD3-CD4-CD8- cells
e. CD3+CD4+CD8+ cells
f. CD3+CD4+ cells
g. CD3+CD8+ cells
h. CD3+CD4+CD25+ cells
i. all of the above
9.
Which cells interaction leads to development of the central tolerance in thymus?
a. thymic epithelial cells with CD3-CD4-CD8- cells
b. thymic epithelial cells with CD3+CD4-CD8- cells
c. dendritic cells with CD3+CD4+CD8- cells
d. dendritic cells with CD3+CD4-CD8+ cells
e. all of the above
10. Which cells interaction leads to development regulatory T cells in thymus?
a. thymic epithelial cells with CD3-CD4-CD8- cells
b. thymic epithelial cells with CD3+CD4-CD8- cells
c. dendritic cells with CD3+CD4+CD8- cells
d. thymic epithelial cells with CD3+CD4+CD25- cells
e. dendritic cells with CD3+CD4-CD8+ cells
11. Which of the following cell types exit thymus?
a. CD3-CD4-CD8- cells
b. CD3+CD4+CD8+ cells
c. CD3+CD4+ CD8- cells
d. CD3+ CD4-CD8+ cells
e. CD3+CD4+CD25- cells
f. CD3+CD4+CD25+ cells
12. Lymphocytes and the Nervous System
Larisa Y. Poluektova
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12. Which of the following interaction affects the survival of T cells in brain?
a. CD95/CD95L
b. CD200/CD200L
c. CD40/CD154
13. Which of the following is NOT considered to be a site of B cells development?
a. thymus
b. bone marrow
c. spleen
d. liver
e. lymph node
14. Which of the following macrophage-secreted cytokines is NOT considered to be stimulators of NK
cells?
a. IL-1
b. IL-10
c. IL-12
d. IL-15
e. IL-18
f. IL-2
15. Which of the following are the major requirements for lymph node development?
a. lymphoid organizer
b. CD45+CD4+CD3- lymphoid tissue inducers
c. LTβR
d. LTα1β2
e. TNF-related activation-induced cytokine (TRANCE)
f. IL-7/IL-7R
g. IL-2
16. Which of the following cell types belong to stromal compartment of lymph nodes?
a. Fibroblastic reticular cells
b. Sinus endothelial cells
c. High endothelial cells
d. T cells
e. B cells
f. DCs
17. Which of the following signaling receptor molecules involved in programming of immunologic memory?
a. CD40
b. CD27
c. CD137
d. ICOS
e. CD28
f. all of the above
18. Which of the following co-signaling molecules involved in programming of peripheral tolerance?
a. CTLA-4
b. BTLA
c. PD-1
d. all of the above
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ANSWERS
1. Briefly summarize the major steps in lymphocyte embryonic development.
The common concept of lymphoid tissue ontogeny results from the understanding that circulating stem/progenitor
cell populations migrate from the yolk sack into the aorta-gonad mesonephros (AGM), then into organ anlages, to
initiate hematopoiesis. Lymphomyeloid commitment precedes thymic development of CD45 + CD117 + CD34 +
hematopoietic clusters in the AGM region. In addition, multi-lineage progenitors restricted to T, NK and macrophage
lineage (pTM) or just T lineage (pT), or B and B plus macrophage (pBM) were identified in the AGM region.
2. Briefly summarize the major steps in T lymphocyte development.
The thymus does not provide an environment for self-renewal. Seeding of the thymus with bone marrow progenitors
is required to maintain thymopoiesis throughout adult life. CD25− (IL-2 receptor alpha chain) and CD117+ expression
have been used to characterize progenitor migration from blood into the thymus. Intrathymic development of T cells
is based on three major sets of genes: promiscuous tissue-specific antigen (TSA) expression on thymic epithelial
cells (TEC), MHC class I and II molecules expression on antigen-presenting cells (APC) such as cortical TEC,
medullary TEC, thymic dendritic cells (DCs) and macrophages, and T cell receptor (TCR) molecule expression on
mature T cells.
3. Briefly summarize the major steps in B lymphocyte development.
B cells are generated from B-lineage committed precursors in the bone marrow (BM). Newly formed B cells express
antigen-specific surface antibody (sIgM+ and sIgD +). Generation of the earliest B cell progenitors depends on
transcriptional factors E2A and EBF that coordinately activate the B cell gene expression program and
immunoglobulin heavy-chain gene rearrangements at the onset of B-lymphopoiesis. Pax5 restricts developmental
options of lymphoid progenitors to the B cell lineage by repressing transcription of lineage-inappropriate genes and
by simultaneously activating expression of B-lymphoid signaling molecules. During B lymphocyte development,
antibodies are assembled by random gene segment re-assortment to produce a vast number of specificities. The
majority (55–75%) of all antibodies expressed by early immature B cells display self-reactivity, including
polyreactive and anti-nuclear specificities. Most auto-antibodies are removed from the population at discrete
checkpoints during B cell development: either immature B cells are eliminated through negative selection (BCRinduced cell death), immature B cells are inactivated (anergy), or immature B cells revise the specificity of their
BCRs (receptor editing).
4. Briefly summarize the distribution of B cells and their function.
Selection of newly formed B cells to transitional, follicular and marginal-zone (MZ) B cells depends on integrated
signals from several classes of surface receptors such as, the BCR and co-signals, the tumor-necrosis factor receptor
(TNFR) family, and the G-protein-coupled receptors (GPCRs). Follicular and MZ long-lived compartments
participate differentially in B-cell effector functions such as the germinal-center (GC) reaction, long-term memory,
antigen presentation, and antibody and plasma-cell (PC) generation.
5. Briefly summarize the major steps in helper cells polarization.
Depending on the co-stimulatory and cytokine signals that are provided by DCs at the time of priming, naive
CD4 + CD25 + T cells differentiate into the different types of helper cells (Th1, Th2, and T follicular helper).
Activation of T cells through the TCR elicits low but detectable transcription of both genes, IL-4 and IFN-γ.
Expression of the T-box transcription factor, T-bet, plays a critical role in Th1 development, and supports
transcriptional competence at the IFN-γ locus and selective responsiveness to IL-12. As stimulation progresses in
the presence of signaling through the essential IL-12 receptor (via transcription factor STAT4), primed cells express
IL-2 and become Th1 helper cells. Transcriptional factor GATA3 is involved in Th2 differentiation and contributes to
chromatin remodeling events that favor IL-4 gene stable demethylation and IL-4 production. Signaling through IL-4
receptor, and downstream with STAT6, favors stable production of IL-4 (as well as IL-5, IL-13) and differentiation in
Th2 cells.
6. Briefly describe the development of central tolerance to myelin.
TEC express tissue-specific antigens representing all parenchymal organs, up to 5–10% of all currently known
genes, including fetal stage-, tumor- and sex-associated genes. TSA expression increases with TEC maturation.
Intrathymal expression of brain antigens such as putative multiple sclerosis (MS) autoantigens B-crystallin, S100,
proteolipid protein (PLP) spliced variant, but not myelin oligodendrocyte glycoprotein (MOG)-α and MOG-β
12. Lymphocytes and the Nervous System
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isoforms were found in the medullary compartment in humans. During ontogeny, oligodendrocytes first express the
fetal form termed golli-MBP, which postnatally is replaced by the adult form, termed classic MBP. The switch from
golli-MBP to classic MBP does not occur in mTECs. Instead, golli-MBP remains the predominant transcript
throughout adulthood, possibly favoring self-tolerance to epitopes present in this isoform. Thus, T cells specific for
epitopes encoded only by the full-length form of PLP or classic MBP may escape intrathymal selection and
contribute to the initiation and maintenance of the early phase of multiple sclerosis.
7. Briefly summarize the major factors that limit T cells survival in the brain.
T cell survival in the brain parenchyma are quickly terminated by neuron-produced gangliosides via the
downregulation of MHC class I and II co-stimulatory molecular expression on glial cells. Several soluble factors can
suppress activation and proliferation of T cells in response to local antigens presented by microglia: vasoactive
intestinal peptide (VIP), IL-10, TGF-β, indoleamine dioxygenase, prostaglandins. T cells could be eliminated from
brain parenchyma via apoptosis mediated by Fas-Fas ligand (CD95/CD95L) interaction. Lymphocyte behavior in
brain tissue depends upon functional status of microglial cells in parenchymal and perivascular macrophages.
Activation of brain microglial cells, DCs and macrophages may also be stopped by factors directly produced by
neurons, such as CD200 molecules, fractalkine. Persistence of T cells in the brain is a rare event and is associated
with chronic pathology forming tertiary lymphoid structures in perivascular spaces, meninges and choroid plexus.
Multiple Choice
8.
i
9.
e
10.
c and d
11.
c and d
12.
a and b
13.
a
14.
b
15.
f
16.
c
17.
f
18.
d