T- & B-cell collaboration

collaboration of T- & B-cell in the thymus

signal 1: BCR & coreceptor (CD19/CD21) interacts with C3b on opsonized microbial surface (antigen dependent)

Signal 2: CD40 (Tfh)

—>antigen dependent, BCR bound structure internalized, cleaved & expressed in MHCII

specific CD4 T-cell activated by antigen that may reside within the viral particle —> recognize surface antigens

B-cell recognizes a surface epitope of a virus, processing & present other antigen epitopes (internalization into phagolysosome & any peptide presented by BCR)

viral-specific Tfh cell provides help to B-cells that recognize a linked epitope

signal 2 antigen but not epitope specific!

migration of a hematopoietic cell from the fetal liver (after birth from the bone marrow) at the place of the lymph node

lymphoid tissue inducer cells Lti

interacts with stromal cells & forms lymph node

each peripheral tissue has a draining lymph node that is created early/before birth

molecules form TNF-SF involved in the crosstalk of stromal cells & Lti (especially TNFα & lymphoid toxin LT)

if receptors TNFR-I or LT-ß receptor KO deficit at the level of SLO

blood passes through the lymph node in a large vessel to decrease the bloodstream allowing extravasation into the lymph node via HEV (high endothelial venules)

naive T-&B-cells first arrive in lymph nodes via HEV & circulate from efferent to afferent lymphatic vessels

B-cells go to the B-cell zone & T-cells to the T-cell zone —> different zones for the lymphocytes after extravasation due to different chemokines

CCR7/CCL21 & then CXCR5(CXCR13 for B-cells (change expression of chemokine receptor)

CCR7/CCL21 for T-cells (B-cells first go into the T-cell zone & then change the receptor)

lymph node encapsulated by subcapsular sinus

size of B-cell follicles depends on the amount of recruited B-cells

efferent lymphatic vessels used by T-cells to travel to other lymph nodes —>cirulate to meet their antigen

other SLO but also other functions (reaction to blood antigens & getting rid of old RBC in red pulp)

immune response in white pulp —> T-&B-cell zone & passing of the bloodstream

antigen delivered via arterioles

antigen uptake by B-cell, macrophages or DC & transport to T- or B-cell zone

opsonized antigens enter lymph nodes from afferent lymphatics & bind to the complement receptors on the surface of macrophages in the subcapsular sinus

free antigen captured by DC or SCS (subcapsular sinus) macrophages (ring of macrophages under the capsule)

the low endocytotic & degradative activity of subcapsular macrophages preserves the antigens trapped on their surface allowing B-cells to encounter them

antigen preservation by sucapsular macrophages also allows antigens to be transported into the follicle to become localised on the surface of follicular DC

FDC not derived from the hematopoietic origin, if no infection no FDC —> cells differentiate into them upon infection

SCS express complement receptor 1 &2 (CR1&2)

no hematopoietic origin —> tissue resident & extremely good at capturing Ag on their surface

if radiolabeled antigen is injected subcutaneously it accumulates at FDC

different antigen processing: no internalization, processing & presentation in MHC

have molecules fixing an antigen after opsonization by CR1 & also captured by antibody & FcR expression

antigen in the form antigen:antibody: complement complex bound to FcR & CR1 or CR2

Activated B-cell induces EBI2 (GPCR)

T-cell induces CXCR5 & both cells migrate to follicular & interfollicular regions

interactions with T-cells sustain EBI2 expression on B-cells which move to outer follicular & interfollicular regions

some B-cells migrate to form a primary focus & differentiate into plasmablasts (1. wave of Ab production) while some T-cells induce Bcl-6 & become Tfh cells

mobility of immune cells mediated by chemokines

in the T-cell zone T-cells are first activated by DC expressing an antigen —>changes chemokine receptor profil from CCR7 to CXCR5 & goes through B-cell zone

FDC changes expression of chemokine receptor like molecule

activated B-cell gains EBI2, when B-&T-cells meet primary focus

don’t form germinal center reaction & differentiate w/o isotype switch to produce Abs rapidly

APC = plasma cell, in between activated & resting state is the plasmablast from the primary focus

Resting B-cell: high in BCR & MHCII, no Ig secretion, massive proliferation possible, somatic hypermutations & class switch

plasmablast: still BCR & MHCII (can interact with T-cell), high rate of Ig secretion, proliferation & class switch

plasma cell: no BCR & MHCII, high rate of Ig secretion, no growth/somatic hypermutation & class switch (terminally differentiated)

activated B-cells at the border of the germinal center enter

centrocytes: contact with FDC & Tfh in the light zone get activated

centroblasts: proliferative cells in the dark (packed) zone (full of activated B-cells)

move after activation from the light to the dark zone (chemokine receptor-dependent)

cyclic reentry of cells into the dark zone depends on reexpression of CXCR4 on centrocytes—>accumulation of mutations

CXCR5+ CXCR4- B-cells in light zone, CXCL13 is the guiding chemokine

CXCR5+ CXCR4+ B-cells after activation & go into the dark zone guided by CXCL12 to proliferate

germinal center specialized for B-cell proliferation, somatic hypermutations & selection for strength of Ab binding

stimulation of CD40 by CD40L induces important genetic events —> DNA mutation

mutate BCR by immune reaction to increase the affinity of interaction with an antigen

mutations observed in CDR1-3 & accumulation of mutations in the germinal center

control location of mutation to prevent oncogenic event (B-cell transformation to cancer —>B-cell lymphoma) —>more frequent than T-cell lymphoma

need selection for increased affinity as mutations are random

antigen at the surface of FDC in the light zone in low concentration —>competition

many proliferating B-cells want to access the antigen —> higher affinity drives selection

some mutations don’t change the affinity & some demolish Ab-specificity —>die due to low affinity & cleared by macrophages

ICOS marker for Tfh —>costimulatory

PD signaling negative regulation —>state of exhaustion preventing proliferation of Tfh restricting T-cell proliferation in the germinal center

DNA in the variable region or in the switch region

transcription produces local ssDNA —>AID can attack in B-cells to deaminate cytidine to uridine —> random mutations —> key enzyme for the immune system

not constitutively activated

mismatch repair enzymes: remove uridine & several adjacent nucleotides

DNAP: fills the gap but is error-prone

AID in association with UNG (uracyl-DNA glycosylase) & APE1 (endonuclease producing ss break)

can also induce B-cell transformation, similar to rearrangement in TCR —> recombination of 2 sites to combine signals

loss of switch sequences to remove everything between the 2 switch sequences

inducing an ss break to allow recombination —> possibility to express other Igs (IgE & IgA)

—>several sequences for the constant part defining the Ig isotype

class switch = DNA recombination, promoter for BCR & Abs strong —> if translocation not correct & strong promotor close to oncogene induction of B-cell lymphomas

AID-dependent DNA rearrangement for class switch

repair proteins act to initiate DSBR —>joins the 2 switch regions & excises intervening sequences

the selected constant region is now located adjacent to the VDJ region

chosen isotype depends on cytokine environment —>favors /inhibits some switches

inhibitory effects probably the result of directed switching to a different class

changes in the constant part & increased affinity are the result of the class switch

—>better Abs with different functions & localization produced

different functions due to Fc receptor

antigens able to induce B-cell differentiation without T-cells

high concentration of TI-1 antigen —> polyclonal B-cell activation & nonspecific Ab response (mitogen independent of BCR e.g. LPS)

B-cell stimulated by 2 signals (signal 2 CD40-independent)—>recognition by BCR & molecule with TLR-ligand —> at high Ag concentration B-cell activating moiety of TI-1 Ag sufficient for activation

at low concentration TI-1 antigen-specific Ab response

can alone signal B-cells to produce IgM

high repetition of 1 epitope—>multiple cross-linking of BCR

activates marginal zone B-cells (between white & red pulp of the spleen) & B1 cells (body cavities)

happen-conjugated polymer

no germinal center reaction —> no somatic hypermutation & class switch