Lec 12: Primary and secondary lymphoid organs Flashcards
What is more important, B cell or T cells?
T cells
these drive and coordiante the immune response
can you survive without either B or T cells? What would be the consequeces?
nopeee youd be bubble boy
Primary lymphoid organs
Thymus= development
and the bone marrow
where the immune cells develop
secondary lymphoid organs
spleen
lymph nodes= activation
= tonsils, adenoids, etc…
wher the adaptive immune responses are initiated
Tertiary lymphoid tissue
site of active infection and or immune activity
de novo lymphoid organs at the site of infection
Immune cell trafficing
know where the cells develop, where they further develop and which organs they develop in
CLPs and the Bone Marrow
required for B cell development
seat of hematopiesis
HSCs =hematopoietic stem cells
stromal cells= support HSCs
Osteoblasts = bone formation and control HSCs
endotheliad cells = line the blood vessel and regulate HSC differentiation
Reticular cells = connect bone and vessels
sympathetic neuron = control the release of HSCs form the bone marrow (central nervous system cross talk)
What is one reason that hematopoeisis decreases with age
with age, fat cells replace 50% of the bone marrow
B lymphocytes develop in the bone marrow
Cytokines involved in B cell differentiation
chemokine CXCL12 is essential for the generation of pre-pro-b and pro-b cells
Il-7 is essential for the generation of pro-B and pre-b cell differentaion
CXCL12 is also involved in homing antibody producing plasma cells to the bone marrow
-> plasma cells take up long-term residence inteh bone marrow and produce ig from within the bone marrow
Development of B cells from the bone marrow to the periphery
HSCs begin their life in close contact with osteoblasts. Once they differentiate into pre-pro-B cells they get the CXCL12 signal from stromal cells as well as a the secretion of IL7 from another stromal cell subset.
rearrangement of the immunoglobulin locus results in pre-BcR receptor and finally a mature BcR
at immature stage, selceiton process to eliminate self ractive B cells
The B cells then mature into follicular B cells (aka marginal zone b cells) in lymph nodes and the spleen
activate antigen specific B cells develop into either plasma cells (anti-body secreting) or memory B cells
negative selection of B cells in movement fromt he bone marrow to the periphery
selection process are in place to kill self-reactive B cell (by apoptosis in the bone marrow)
Thymus
T cells develop initially in the bone marrow but then migrate to the thymus to achieve full maturity
T cell Trafficking in the thymus
circulating T cell progenitors enter vi athe vasculature in teh corticory-medullary junction
CD4-CD8 double negative (DN) thymocytes migrate inot the capsule due to CXCR4 and CCR7 mediated chemotaxis
migration into the subcapsular zone mediated by CCR9 signals (deeper and deeper into the tissue)
CD4+CD8+ double positive (DP) thymocytes interact with cortical thymic epithliad cells (cTEC) for positive and negative selection
Positively selected DP tymocytes differentiate inot CD4+ or CD8+ single positive cells (SP) increased CCR7+ allows for migration towrds the medulla expressing CCR7 ligands
Further selection of SP thymocytes includes the deltion of tissue specific antigen-reactive T cells and the generation of regulatory T cells
matrue SP T cells expression sphingosine-1-phosphate receptor 1 (S1P1) guiding them to the circulation
Purpose of cTEC
these are cortical thymic epithelial cells
they aid in positive and negative selection of T lymphocytes
the are APCs that present self-antigens and will kill T-cells if they react to those self-antigens
corticor-medullary junction
where the circulating T cell progenitors enter the thymus
What cytokine induces double-negative T cells to migrate in the capsule
CXCR4 and CCR7 mediated chemotaxis
what is a double negative T cell
Lacks CD4 and CD8
What cytokine triggers DN T cells to migrate into the subcapsular zone
CCR9
What happens to T cells immediately after interacting with cTEC cells
positively selected double-positive cells differentiate into CD4 or CD8 single-positive cells
then, increases CCR7+ allows for migration towards the medulla expressing CCR7 ligands`
AIRE
autoimmune regulator (AIRE) is a key TF in the thymus
AIRE binds to non-methylated histone 3 lysine 4 (H3K4), which marks promoters in closed chromatin regions (Non-expressed genes)
TRAs
Tissue-restricted antigens
expression of tissue-rejected antigens in medullary thymic epithelial cells `(mTECs)
Thymocytes that react strongly to TRAs are negatively selected to undergo apoptosis, or they are redirected to become Treg cells
however around 5% can still be autoreactive
mTEC
medullary thymic epithelial cell\
single positive thymocytes circulate in the medulla for about 5 days and encounter several hundred mTECs expressing various TRAs
mTECs share their TRAs with other mTECs, as well as with DCs
which receptor helps to guide mature SP T cells towards circulation
sphingosine-1-phosphate receptor 1
What happens to thymocytes that survive positive and negative selection not he thymus
they leave the thymus as naive t cells
Treg also leave the thymus and are involved in maintaining tolerance
autoreactive Treg could however break tolerance and induce autoimmune disease
if you cut your finger where do the foreign antigens go? How do they get to their final destination
???
Purpose of secondary lymphoid organs
areas where lymphocytes encounter antigen, become activated, undergo clonal expansion, and differentiate into effector cells
these organs include:
- lymph nodes
- spleen
- mucosa-associated lymphoid tissue (MALT)
- other diffuse and loosely organized areas
they are connected to each other via the blood and lymphatic circulatory systems
which chemokines are essential for homing T cell to the lymph nodes
CCR7
Which chemokine recru9its T cells back to circulation
S1PR1
HEV
high endothelial venule
read pg 57-60
and fig 2-13
Organization of Lymph nodes
T cell and B cell activity are separated into distinct microenvironment
The cells will actively migrate toward each other during activation events that require B cell - T cell interactions
Cortex: B cells, macrophages and follicular DCs arranged into follicles
Paracortex: T cells and DCs
Medula: egress for lymphocytes
Antigens enter B cell zone via the afferent lymph
antigen is taken up by resident SCS (subcapsular sinus) macrophages and follicular DC’s
B cells can respond to free antigens or antigen complexes (intact antigen)
Migrating DCs bring antigen to the T cell zone
Migrating DCs entering via the HEV…
DCs can present intact antigen to B cells
DCs can present processed antigen to T cells
Migrating DCs can pass antigen to resident DCs in the para cortex
B cell and T cells migrate in the paracortex via processes that arise from fibroblast reticular cells (FRCs)
Germinal Center (GC)
Area within secondary lymphoid organs where mature B cells proliferate and differentiate and mutate their antibody genes => affinity maturation
(issa sub-sect of a B-cell follicle)
Dark zones: proliferating B cells undergoing somatic hypermutation
Light zones: B cells bidn antigen on FDCs and receive survival signals form Th cells
SHM
somatic hypermutation
occurs when B cells mutate their antibody genes
this is essential for the production of high-affinity antibodies
Follicular DCs in Germinal centers
will be on the final
FDCs = non-haematopoietic cells
are integrated into the continuous stromal network within lymphoid organs
acquire antigens, which are retained in their native form for long periods of time (non-degenerative endosomal vesicles periodically cycle antigen to the cell surface)
Retention of antigen by FDCs is important for an efficient germinal center reaction
how does Th cell parring occur
during the formation of GCs, activated B cells engulf cognate antigen and present it to T cells in the paracortex
if successful Th cell parring occurs, prolonged interaction promotes B cell proliferation
What does BCR somatic mutation allow
for affinity maturation to occur in the GC
Generates B cells with improved antibody specificity for antigen
affinity maturation is the process by which TFH cell-activated B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce antibodies of successively greater affinities
What is the final outcome of B cell - T cell interaction in the GC
some B cells become memory cells
Plasma cells will travel to medulla or bone marrow to secrete antibodies
memory B cels can reside in the lymph node or recirculate
How long can the establishment of the GC take
how long will they remain active for
4-7 days to establish
can remain active for 3+ weeks
X-associated lymphoid tissue
lymphoid follicles can be found in mucosal membranes of digestive, respiratory and urogenital tracts (type I) and the skin (type II) epithelium
M (Microfold) cells are specialized to transport antigen across type I epithelium
Pocket of DCs, B cells and T cells resides below the M cells and sample incoming antigens
BALT
bronchus associated lymphoid tissue
MALT
Musoca associated lymphoid tissue
iBALT
inducible bronchus associated lymphoid tissue
NALT
nasal associated lymphoid tissue
GALT
gut associated lymphoid tissue
IEL
intraepithelial lymphocytes
