B cell memory

Tae Jin Kim

B cell function Antibody production of appropriate specificity (highly specific Ab, multispecific Ab) B cell antigen receptor & membrane-bound immunoglobulin

1. Signaling for development, maintenance & proliferation2. Endocytosis and antigen presentation

(NI,2:480,’01)

(COII,12:276,’00)

Role of BCR & preBCR; check Ig gene rearrangementSignals the successful gene rearrangementNature of signal; constitutive, regardless of antigen (or ligated by a certaine ubiquitous ligand

(NRI,5:230,’05)

Antigenic encounter

Naïve B cell

Plasmoblast,movement to medullary cord

Entrance into B cell follicle/GC formation

Memory cell

Plasma cell

Plasma cell

T cell-dependent response

T cell-independent responses TI-I antigen; polyclonal B cell activator such as LPS TI-II antigen; repeating determinants on a large polysaccharide backbone, present on H. influenzae, Streptococcus

costimulation given by innate immunity (not by T cells)

(Immunol Rev,194:48,’03)

(NRI,5:230,’05)

Immunological memory;

not necessary? Zinkernagel “Immunological memory is unimportant for the survival of the individual and instead evolved as a means of intergenerational transfer of immune function.”

“If an unprimed host survives an initial infection, the host does not really need immunological memory to survive the second infection.”

Intergeneration transfer of immune function; transfer of immunoglobulin from mother to fetus, innate lymphocytes

Immunological memory;

important!! Not all infections are deterministic.; “Low responders always die of an infection, while high responders always survive repeated infection.”

In reality, survival is a stochastic process in which even minor illnesses may increase the probability of death. If immunological memory reduces the severity/length of a second infection, it provides a distinct survival advantage.

Value of Immunity; not only survival, but also fitness

(NI,1:451,’00)

Immunological memory

Speed, size, persistence

Results of complex immunological networks; cannot be explained by just the presence of memory lymphocytes

Definition of memory lymphocytes

Central memory and effector memory

(NI,6:866,’05)

How are memory cells maintained?

Survival Prolonged survival may not be guaranteed.

Low-level proliferation and compensation of stochastically dying cells (attrition)

Repeated antigenic exposure and clonal expansion

Chronic antigenic exposure leads to immune exhaustion.

Residual antigen trapped by DCs and FDCs

Immunological memory

(COII,16:217,’04)

(COII,17:326,’05)

Features of Memory T cell

Stem cell-like properties

More efficient response to the antigen

Dependence on cytokine (IL-15 for CD8+ memory T cells); naïve cell dependent on IL-7

Persistence of memory T cell in the absence of MHC

Homeostasis of T cell pools(NRI,4:387,’04)

B cell memory

Memory B cell; quiescent B cells derived from proliferating antigen-experienced precursors, capability of self renewal?

Memory plasma cell; long-lived plasma cells in bone marrow

B cell population dynamics (I)

- rate of B cell production; 4-5 days sufficient to replenish the recirculating pool if no recirculating B cells are present (Int Immunol,1:321,'89)

- actual rate of replacement; as much as cell loss of recirculating B cell pool

(More than 90% of immature B cells fail to receive selection signal.)

- transfer of recirculating B cells into SCID mouse

Bone marrow

PeripheryShort lived naïve B cells

Fail to enter lympoid follicleHalf life of about 3 days

Entrance into folliclesLong-lived naïve B cells

Simulation by antigen

Follicular exclusion of autoreactive IgM+ B cells

B cell population dynamics (II)

(COII,15:354,03)

B cell layers in mouse

B1a cell; natural antibody, autoreactive and against common epitopes

B1b cell; antibody against bacteria, development after birth

B2 cell; most advanced B cell, the highest affinity to a given protein antigen

Marginal zone B cell; develop after birth, strategic location in spleen to fight against bacteria in blood

(NRI,5:230,’05)

Differentlevels of memory

(NI,7:225,’06)

B220+ CD43+

B220+ CD43-

R9-pro pre B

R10-early B

R11-late B

R6-pre B

R7-B

BM

Innate B cell

Memory from ancestors

No memory in the Individual basis; no memory cell formation after primary antigenic encounter

Constitutive antibody secretion by B1a cells

In the case of B1b cells, there seems to be a memory immune response on individual basis.

Characteristics of memory B cell

Lower threshold for activation, longer life span

No requirement for antigen for its maintenance

Higher expression of signaling molecules than naïve B cells

Biased toward terminal differentiation

Expression of CD27, class switching, hypermutation

CD27 as a marker of human IgM+ B cells.

Hypermutation in CD27+ B cells

B cell; antigenic encounter --> class switching, hypermutation (Sometimes, B cells may acquire hypermutation without class switching and become IgM+ memory B cells.

(JEM,188:1679,’98)

Now appears to be wrong

Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire (Blood,104:3647,’04)

CD27 is not expressed on most of mouse spleen and blood B cells.

CD27 was only expressed on a subset of larger B220+ cell, but not on most resting recirculating B cells.

CD27 was regulated by shedding Induced by extracellular ATP.

CD27 was expressed on a subset of B1a cells.

Surface expression of CD27 on B-1 cell after stimulation with LPS

No treat

LPS IP

Surface expression of CD27 on B cell in neonate mice

CD11b+ IgM+ IgM+

Conclusion There are several layers of B cells, each of which has a

certain specific function.o B1a cell; continuous production of natural antibodyo B1b cell; immediate response to common pathogen such as Borrelia, antib

ody production when askedo MZ B cell; immediate response to blood pathogen, antigen presentationo B2 cell; late high-affinity humoral response to a variety of antigens,

requires T cells for function

Therefore, there are different layers of B cell memory.o B1a cell; memory from ancestor, little fluctuation with antigeno B1b cell; short-term memory response, long-term memory without antigen

(?)o MZ B cell; leave MZ after activation, recruitment of new MZ B cells fro

m developing transitional B cellso B2 cell; memory cell generation (class switched, hypermutated), We do n

ot know well about this.; long-lasting without antigen? Memory cells in the periphery?

o Differentiation into memory B cell or plasma cell (and then to memory plasma cell)