LECTURE:24March2023

TCR expression is controlled by allelic exclusion

--Allelic exclusion is a process by which only one allele of a gene is expressed while the
other allele is silenced.
--Allelic exclusion occurs among TCR genes almost as effi ciently as among BCR genes,
with one exception: some fraction of T cells bear more than one αTCR chain.
---However, it would be unlikely, although not impossible, that a T cell bearing two α
chains would be able to recognize more than one antigen, given the complexity of T-cell
antigen recognition.

---TCRs are tested twice within the thymus to determine their functionality before the
T cells are released into the periphery.
---First, T cells are tested to ensure that the alpha and beta chains can pair into a
functioning TCR that is capable of recognizing self MHC antigens bearing self peptides
with low to moderate affi nity (positive selection).
--Th en, T cells bearing receptors that recognize self peptides in association with MHC
antigens at high affi nity are eliminated in order to eliminate the generation of
autoreactive receptors (negative selection).
--Th e likelihood that a single TCR βchain could pairwith more than one TCR αchain
ameet all these stringent criteria is extremely small.
---Th e presence of even one TCR capable of binding self antigens at high affi nity would
result in the elimination of the cell, irrespective of the specifi city of the receptor formed
using an alternative α chain
---- Although B and T cells use very similar mechanisms for variable region gene
rearrangements, complete rearrangement of Ig genes does not occur in T cells and
complete rearrangement of TCR genes does not occur in B cells
---Not only is the recombinase enzyme system diff erently regulated in each
lymphocyte lineage, but chromatin is uniquely reconfi gured in B cells and T cells to
allow the recombinase access only to the appropriate specifi c antigen receptor genes.

-- expression of TCR genes requires the coordinated use of transcriptional promoters

and enhancers that serve at specifi c stages in T-cell development to make the
receptor chromatin open and accessible for recombination(see Chapter 9).
----T cells begin to rearrange the TCR β gene at the pro-T-cell stage.
---Th e mouse TCRβ locus (see Figure 7-18) consists of approximately 40 V β genes
located upstream of 2 distinct D β J β clusters.
--- Immediately upstream of each of the two D β genes is a promoter region (PD1 and
PD2).
---Th ese promoters require the activity of a single enhancer, E β, located at the 3’end
of the locus. Activation of the enhancer serves to facilitate the opening of the
chromatin throughout the D β J β locus, and activation of each of the two PD promoters
localizes the rearrangement to their own set of DJ regions.
-----Several TCR enhancer-binding proteins have been identified-- some of these are shared
among cells of many diff erent types.
---Among the T-cellspecifi c proteins is GATA-3, which binds in a sequencespecific manner
to the enhancer elements of all four TCR genes.
---Tissue- and stage-specifi c expression of enhancerbinding proteins at the TCR loci helps
to facilitate locus accessibility that in turn allows the complex processes of recombination
and transcription of the TCR genes and, eventually, cell-surface expression of the TCR
proteins.

---mutations in the genes encoding RAG1 or RAG2 have catastrophic consequences for the
immune system, resulting in patients with severe combined immunodefi ciency, or SCID.
The RAG1/2 genes are located on human chromosome 11 (i.e., an autosome), so
such mutations are inherited in an autosomally recessive manner.

--Babies born with nonfunctional RAG1 or RAG2 genes have essentially no circulating
B or T cells
-----infants receive antibodies passively from the maternal circulation, the fi rst
manifestation of this disease is the complete absence of T-cell function, and
hence such infants suff er from severe, recurrent infections with fungi and viruses
that would normally be combated by T cells in a healthy neonate.
----SCID is fatal within the fi rst few months of life, unless babies were delivered
directly into a sterile environment….short-term measure.
----RAG1/2 defi ciency can be successfully treated with bone marrow transplantation
within the 1st year after birth..
Patients who carry mutations resulting in partially active or impaired RAG1 or
RAG2 genes are diagnosed with Omenn syndrome.
---they have oligoclonal T cells (derived from a very few precursors and hence have
very few different receptors), and these T cells tend to be inappropriately activated.
----they also require bone marrow transplantation.

---loss of any of the other genes implicated in V(D)J recombination

would also result in a SCID phenotype.
---In early fetal life, the lymphocyte development originates from stem cells found in the
fetal liver and in even more primitive hematopoietic tissues in the developing embryo.

-- B and T cells that develop from these early fetal progenitors generally populate
mucosal and epithelial tissues and function in innate immune responses. In the adult,
these subsets of lymphocytes are minority populations in secondary lymphoid tissues.

----In fetus and the juvenile, the central lymphoid tissues are the sources of large
numbers of new lymphocytes, which migrate to populate the peripheral lymphoid
tissues (also called secondary lymphoid tissues) such as lymph nodes, spleen, and
mucosal lymphoid tissue. –3

----In mature individuals, the development of new T cells in the thymus slows down, and
peripheral T-cell numbers are maintained by the division of mature T cells outside the
central lymphoid organs.--4

--New B cells, in contrast, are continually produced from the bone marrow, even in
adults.

----We now know that the B- and T-cell development that predominates--2
during late fetal life and after birth is distinct from lymphocyte (occurs as waves)
development that take place earlier in fetal ontogeny. --!
--Range of pathogens to which we are exposed is tremendously diversse
--so to combat that vertebrates also generate a comparable range of T-cell (and B-cell)
receptor specifi cities.
--Each of the several million T cells circulating in the body expresses a distinct T-cell
Receptor.

--The generation of this diverse population, with its diverse receptor repertoire, takes place
in the thymus, an organ both required for and dedicated to the development of T cells.

---Immature cells entering the thymus from the bone marrow express no mature
lymphocyte features and no antigen receptors.
---those leaving the thymus are mature T cells that are diverse in their receptor
specificities, and are both tolerant to self-peptides and restricted to self-MHC.

How do we generate such a diverse self-restricted and self-tolerant group of T cells?

--Study how THYMUS is nursing immature T cells also called thymocytes and produces
functional, safe and useful T cell repertoire.
--T-cell development into two clusters of events:
--early thymocyte development, during which a dizzyingly diverse TCR population of
immature T cells is generated, and
--selection events that depend on TCR interactions to shape this population so that
only those cells that are self-restricted and self-tolerant will leave to populate the
periphery.

---Early thymocyte development is T-cell receptor independent and brings cells

through uncommitted CD4CD8 (double negative, DN) stages to the T-cell receptor-
expressing, CD4CD8 (double positive, DP) stage. The specific events in this early stage
include:
1. commitment of hematopoietic precursors to the T cell lineage,
2. the initiation of antigen receptor gene rearrangements, and
3. the selection and expansion of cells that have successfully rearranged one of their
T-cell receptor genes (-selection).

---Th e second phase of T-cell development is largely dependent on T-cell receptor

interactions and brings cells to maturity from theDP CD4CD8 stage to the CD4 or CD8
single positive (SP) stage. Th e events in this last phase of development include:
1. positive selection, selection for those cells whose T-cell receptors respond to self-
MHC,
2. negative selection, selection against those cells whose T-cell receptors react
strongly to self-peptide/MHC combinations, and
3. lineage commitment, commitment of thymocytes to effector cell lineages, including
CD4 helper or CD8 cytotoxic populations.
The production of new lymphocytes, or lymphopoiesis, takes place in
specialized lymphoid tissues—the central (or primary) lymphoid tissues—
which are the bone marrow for most B cells and the thymus for most T cells.

--Precursors for both populations originate in the bone marrow

--B cells complete most of their development in bone marrow,
---the precursors of most T cells migrate to the thymus, where they develop into
mature T cells.

--T-cell development in the thymus has some features not seen for B cells, s
1. Generation of two distinct lineages of T cells expressing TCR’s encoded by distinct
genes, the γ:δ lineage nd the α:β lineage.
2. Developing T cells, which are known generally as thymocytes, also undergo rigorous
selection that depends on interactions with thymic cells and that shapes the mature
repertoire of T cells to ensure self-MHC restriction as well as self-tolerance

---A major goal of lymphopoiesis is to generate a diverse repertoire of B-cell receptors

and T-cell receptors on circulating B and T cells, respectively, thereby enabling an
individual to make adaptive immune responses against the wide range of pathogens
encountered during a lifetime.

T-cell development purpose is to the central purpose of the process:

to generate a large population of T cells that express a diverse array of receptor specifi
multipotent hematopoietic stem cells (HSCs) inn bone marrow Stem cells are Self-renewing
cell-surfacereceptor tyrosine kinase MPPs express transcription factors and receptors that are
known as FLT3 that binds the Multi-potent progenitor required for the development of multiple ematopoietic
membrane-bound FLT3 ligand on lineages, such as the transcription factor PU.1 and the
stromal cells receptor c-kit.

common lymphoid progenitor cells

lymphoid lineage—B cells lineage, T cell lineage and another is

the innate lymphoid cell progenitors
basic principles of cell differentiation -Properties that are essential
for the function of the mature cell are gradually acquired, along with the loss
of properties that are more characteristic of the immature cell.

specialized microenvironment of the organ signals act on the developing lymphocytes to

switch on key genes that direct the developmental program
These signals are produced by the network of specialized nonlymphoid connective
tissue stromal cells that are in intimate contact with the developing Lymphocytes

The contribution of the stromal cells is twofold. First, they form specific adhesive contacts
with the developing lymphocytes by interactions between cell-adhesion molecules and their
ligands. Second, they provide soluble and membrane-bound cytokines and chemokines
that controllymphocyte differentiation and proliferation
The thymus, which lies in the midline of the body, above the heart, is made up of
several lobules, each of which contains discrete cortical (outer) and medullary (central)
regions
In young individuals, the thymus contains large numbers of developing T-cell precursors
embedded in a network of epithelia known as the thymic stroma.
--This provides a unique microenvironment for T-cell development analogous to that
provided for B cells by the stromal cells of the bone marrow.
The cellular architecture of the human thymus is illustrated in Fig. 8.16.
---Bone marrow-derived cells are differentially distributed between the thymic cortex
and medulla.
---The cortex contains only immature thymocytes and scattered
macrophages, whereas more mature thymocytes, along with dendritic cells,
macrophages, and some B cells, are found in the medulla.
---this organization reflects the different developmental events that occur in these
two compartments.
--knowledge of T-cell development in the thymus comes from the mouse:
In mouse model: nude mutation results in Absent thymus (athymia), alopecia
universalis (AU) and nail dystrophy were first noted in 1966 in a spontaneously
occurring phenotype in the so-called nude mouse.
Subsequently, human counterpart of the nude phenotype was reported with early-
onset severe immunodeficiency- DiGeorge syndrome
--both DiGeorge syndrome in humans and in mice with the nude mutation-- the
thymus does not form and the affected individual produces B lymphocytes but few T
lymphocytes.
---Both cases there is a defect in gene /deletion of chromosome region coding for
Foxn1, a transcription factor required for terminal epithelial cell differentiation or
---In humans- DiGeorge syndrome is associated with T-cell immunodeficiency, absence of
a thymus, congenital alopecia, and nail dystrophy.
-
--FOXN1 is required for the development of epithelial cells in the thymus, the skin, hair
and nails. As the developmental defect of TECs results in a lack of regular T-cell
development and selection, FOXN1 deficiency has been classified as a rare form of severe
combined immunodeficiency (SCID) with absent or low T-cells (i.e. a T-/lowB+NK+ SCID).

--SCID syndromes are an aetiologically heterogeneous group of genetic disorders, defined

by defects in T-cell development and function and a variable impact on the development
of B- and NK-cells [20].

-- Consequently patients are unable to produce protective immune responses and present
in early infancy with life-threatening infections [20].
----Nude SCID is an example of a SCID syndrome that is not due to mutation of a gene
expressed in hematopoietic cells but rather constitutes an abnormality of the thymic
stromal cell compartment, namely TECs, essential for normal T-cell development
--In mice, the thymus continues to develop for 3–4 weeks after birth, whereas
in humans it is fully developed at birth.
---The rate of T-cell production by thethymus is greatest before puberty.
--- After puberty, the thymus begins to shrink, and the production of new T cells in
adults is reduced, although it does continue throughout life.

---In both mice and humans, removal of the thymus after puberty is not
accompanied by any notable loss of T-cell function or numbers.
----Thus, it seems that once the T-cell repertoire is established, immunity can be
sustained without the production of significant numbers of new T cells; the
pool of peripheral T cells is instead maintained by long-lived T cells and also
by division of some mature T cells.
common lymphoid progenitor cells present in bone marrow
1. Some of these progenitors leave bone marrow and migrate to thymus

2. In thymus, the progenitor cell receives a signal from thymic epithelial cells
that is transduced through a receptor called Notch1 to switch on specific
genes for differentiation i.e. commit to T cell lineage.

3. Notch signaling is required throughout T-cell development

T cell lineage
Notch signaling is essential to initiate the T-cellspecific gene expression program and
commitment to the T-cell lineage (Fig. 8.18).
---First, Notch signaling induces the expression of two transcription factors, T-cell factor-1
(TCF1) and GATA3, each of which is required for T-cell development. Together, TCF1 and GATA3
initiate expression of several T-lineage-specific genes, such as those encoding components of
the CD3 complex, as well as Rag1, a gene required for T-cell receptor and B-cell receptor gene
rearrangements (see Fig. 8.18).
----However, TCF1 and GATA3 are not sufficient to induce the entire program of T-cell-specific
gene expression.
---A third transcription factor, Bcl11b, is required to induce T-lineage commitment by
restricting progenitor cells from adopting alternative fates; this final phase of T-cell
commitment is a necessary prerequisite for activating the complete T-cell gene expression
program
During the time it takes cells to develop in the thymus (1 to 3 weeks), thymocytes pass
through a series of stages defined by changes in their cell surface phenotype (see
Overview Figure 9-1).
Th e earliest T cells lack detectable CD4 and CD8 and are therefore referred to as
double-negative (DN) cells.This is divided into 4 sub-stages based on expression of c-
kit(CD117, receptor for stem cell growth factor) and CD44- an adhesion molecule, CD25-
alpha chain of IL-2 receptor.
---DN1: thymocytes are the first to enter the thymus and are still capable of giving rise to
multiple cell types. Th ey express only c-kit and CD44 (c-kit++CD44++CD25-), but
once they encounter the thymic environment and become resident in the cortex, they
proliferate and express CD25 becoming DN2 thymocytes (c-kit++CD44+CD25+). in these
cells
In these DN2 thymocytes ---the genes for the TCR γ,δ, β chains begin to rearrange;
however, the TCR α locus does not rearrange, presumably because theregion of DNA
encoding TCR genes is not yet accessible to the recombinase machinery.
--At the late DN2 stage, T-cell precursors fully commit to the T-cell lineage and reduce
expression of both c-kit and CD44.
--- Cells in transition from the DN2 to DN3 (c-kit+CD44-CD25+) stages continue
rearrangement of the TCRβ, TCRγ, and TCRδ chains and make the fi rst major decision in
T-cell development whether to join the TCRαβ or TCRγδT-cell lineage.
--Those DN3 T cells that successfully rearrange(in-frame VDJ joining)their β chain
---commit to the TCRαβ T-cell lineage (Expression of pre-TCR; β-selection) will loose
expression of CD25 and halt proliferation and enter
---- enter the fi nal phase of their DN stage of development, DN4 (c-kitlow/-CD44-CD25-),
which mature directly into CD4+CD8+ DP thymocytes.
---this stage is marked by Proliferation, allelic exclusion of β–chain locus; α-chain locus
rearrangement begins; becomes DP thymocyte

The earliest precursor thymocytes enter the thymus from the bloodstream via venules
near the cortico-medullary junction.

Ligands that interact with the receptor Notch1 are expressed in the thymus and act on
the immigrant cells to commit them to the T-cell lineage.

As these cells differentiate through the early CD4–CD8– double-negative (DN)stages

described in the text, they migrate through the cortico-medullary junction
and to the outer cortex.

DN3 cells reside near the subcapsular region, where they undergo proliferation. As the
progenitor matures further to the CD4+CD8+ double positive stage, it migrates back
through the cortex.

Finally, the medulla contains only mature single-positive T cells, which eventually leave
the thymus.
---Vertebrates generate two broad categories of T cells: those that express TCRα andβ
receptor chains and those that express TCR γ and δ receptor chains.
---TCR αβcells are the dominant participants in the adaptive immune response in
secondary lymphoid organs; however, TCR γδ cells also play an important role,
particularly in protecting our mucosal tissues from outside infection.
---Both types of cells are generated in the thymus, but how does a cell make the decision
to become one or the other?

---To a large extent, the choice to when and how fast the genes that code for each of the
four receptor chains successfully rearrangei.e. DN3 stage

---Recall from Chapter 7 that TCR genes are generated by the shuffl ing (rearrangement)
of V and J (and sometimes D) segments, an event responsible for the vast diversity of
receptor specifi cities.
-----Rearrangement of the β, γ, and δ loci begins during the DN2 stage.
---To become an αβT cell, a cell must generate a βTCR chain—an event that depends on
a single in-frame VDJ rearrangement event.
--To become a γδcell, however, a thymocyte must generate two functional proteins that
depend on two separate in-frame rearrangement events.
---Probability favors the former fate and, in fact, T cells are at least three times as likely
to become TCR αβcells than TCRγδ cells.
Most TCR
TCRγδ T-cell generation is also regulated developmentally.
Th ey are the fi rst T cells that arise during fetal development, and provide a very
important protective function perhaps even prior to birth. Studies show, for
instance, that T cells are required to protect very young mice against the protozoal
pathogen that causes coccidiosis.
However, production of γδT cells declines aft er birth, and their population
represents only 0.5% of all mature thymocytes in the periphery of an adult animal
(Figure 9-3).

DN-CD4-CD8- --Fetal animals generate more γδ T cells

thanαβ T cells, but the proportion
of γδ T cells generated drops off dramatically
DP-CD4+CD8+
after birth.
---This early dominance of γδ TCR cells may
have adaptive value: a large portion
of these cells express non- diverse TCR specifi
cities for common pathogen proteins and can
mount a quick defense before the more
traditional adaptive immune system has fully
developed.
Double-negative (DN) stage 3 thymocytes that have successfully rearranged their
TCR β undergo expansion via a process known as β-selection (see Overview Figure 9-
1).

--Th is process involves a protein that is uniquely expressed at this stage of

development, a 33-kDa invariant glycoprotein known as the pre–T α chain.
--Pre-Tα acts as a surrogate for the real α TCR chain, which has yet to
rearrange, and assembles with a successfully rearranged and translated βchain, as
well as CD3 complex proteins. Th is precursor TCR/CD3 complex is known as the
pre-TCR(Figure 9-4a) and acts as a sensor by initiating a signal transduction
pathway. Th e signaling that the pre-TCR complex initiates is dependent on many of
the same T-cell specific kinases used by a mature TCR but does not appear to be
dependent on ligand binding.
-- successful assembly of the pre-TCR complex with little if any expression on cell
surface aactivates signaling events.
Pre-TCR signaling results in the following cascade of
events:
1. Maturation to the DN4 stage (c-kitlow/CD44-CD25-)
2. Rapid proliferation in the subcapsular cortex
3. Suppression of further rearrangement of TCR β–chain genes, resulting in allelic
exclusion of the β –chain locus. Allelic exclusion is a process by which only one
allele of a gene is expressed while the other allele is silenced.
4. Development to the CD4CD8 double-positive (DP) stage
5. Cessation of proliferation
6. Initiation of TCR α chain rearrangement

---It is important to note that the proliferative phase prior to αchain

rearrangement enhances receptor diversity considerably by generating clones of
cells with the same TCRβ-chain rearrangement.
---Each of the cells within a clone can then rearrange a diff erent α-chain gene,
thereby generating an even more diverse population than if the original cell had
undergone rearrangement at both the α- and β-chain loci prior to proliferation.
TCRα -chain gene rearrangement does not begin until double-positive thymocytes
stop proliferating.
Most T cells fully rearrange and express a TCR chain
from only one of their two TCR alleles, a phenomenon
known as allelic exclusion. Allelic exclusion is the result of
inhibition of further rearrangement at the other TCR
allele (which must be fully rearranged to be expressed).
Th is can be accomplished by reducing RAG expression so
no more rearrangement can occur, as well as by making the
locus inaccessible to further RAG interaction via more
permanent changes in chromatin packaging. Th e details of
the mechanisms responsible for this shutdown are still
being investigated. However, negative feedback signals
from a successfully assembled pre-TCR/pre-T complex
during -selection clearly have a signifi cant infl uence.
Other events, including the proliferative burst that follows
-selection, which dilutes RAG protein levels, can also play
a role.
RAG levels continue to change aft er -selection. Th ey are
restored aft er the proliferative burst and allow TCR rearrangement
to occur. Th ey decrease once again aft er expression
of a successfully assembled TCR dimer.
 ---When progenitor cells first enter the thymus from the bone marrow,
---Haematopoeitic precursors/ common lymphoid progenitors
---they lack most of the surface molecules characteristic of mature T cells---
----- Arrive at thymus ---Interactions with the thymic stroma trigger an initial phase of
differentiation along the T-cell lineage pathway,
----followed by cell proliferation and the expression of the first cell-surface molecules specific
for T cells, for example, CD2 and (in mice) Thy-1.
---At the end of this phase, which can last about a week, the thymocytes bear distinctive
markers of the T-cell lineage but do not express any of the three cell-surface markers that
define mature T cells. These are the CD3:T-cell receptor complex and the co-receptors CD4
or CD8.
---Because of the absence of CD4 and CD8, such cells are called double-negative thymocytes

--- and their receptor genes are not rearranged.

--These cells give rise to the major population of α:β T cells and the minor population of γ:δ
T cells.

---If injected into the peripheral circulation, these lymphoid progenitors can even give rise to
B cells and NK cells,
---In the bone marrow the HSC give rise to haematopoetic precurrsor which arrive in the
thymus.
--Haematopoitic precursors are directed by chemokines to thymus.
---they have the ability to differentiate into many cell types like NK cells, DC,B cells and
myeloid cells and commt to T cell lineaage only at DN2 stage.
---Commitment to T cell lineage depends on Notch receptor (classic function in embryonic
development).
---the decision of a lymphoid precursor to become a T versus a B lymphocyte. When a
constitutively active version of Notch1, one of four versions of Notch, is overexpressed in
hematopoietic cells, T cells rather than B cells develop in the bone marrow. Reciprocally,
when the Notch1 gene is knocked out among hematopoietic precursors, B cells rather than
T cells develop in the thymus (!).

--in vitro system for studying T-cell development without intact architecture of the thymus.
----iearly studiesused intact fetal thymic organ culture systems.
----2002, J. C. Zuniga-Pfl uker and colleagues demonstrated growth of hematopoietic stem
cells (HSCs) on stromal cells that express Notch ligand drives the development
of these multipotent stem cells to the T-cell lineage.
------discover defining interactions that control early T-cell development and have helped
investigators reveal, for instance, that the transcription factor GATA-3 is a critical participant
in Notch-mediated T-cell commitment
--Spatial and temporal regulation of T cell development in thymus
i.E Diff erent stages of development take place in distinct microenvironments that
provide membrane-bound and soluble signals that regulate maturation.

--Hematopoetic precursors(earliest thymocytes) arrive from bone marrow by

blood via venules near cortico-medullary boundary/junction of thymus.

---T-cell precursors fi rst travel to the outer cortex where they slowly proliferate,
then they pass through the thymic medulla before exiting at the orticomedullary
Junction.
---it takes about 1-3 weeks for T cell devlopment.

---Ligands that interact with the receptor Notch1 are expressed in the thymus and
act on the immigrant cells to commit them to the T-cell lineage.

---When progenitor cells first enter the thymus from the bone marrow, they lack
---Th e earliest T cells lack detectable CD4 and CD8 and are therefore referred to
most of the surface molecules characteristic of mature T cells, and their receptor
as double-negative (DN) T cell which are divided into 4 types- DN1-4 on the basis
genes are not rearranged.
of expression of the adhesion molecule CD44, CD25 (the α chain of the IL-2
receptor), and Kit, the receptor for SCF.
--These cells give rise to the major population of α:β
T cells and the minor population of γ:δ T cells. If injected into the peripheral circulation,
these lymphoid progenitors can even give rise to B cells and NK cells,
--In fetus and the juvenile, the central lymphoid tissues are the sources of large
numbers of new lymphocytes, which migrate to populate the peripheral lymphoid
tissues (also called secondary lymphoid tissues) such as lymph nodes, spleen, and
mucosal lymphoid tissue. --3

--In mature individuals, the development of new T cells in the thymus slows down,
and peripheral T-cell numbers are maintained by the division of mature T cells
outside the central lymphoid organs.--4

--New B cells, in contrast, are continually produced from the bone marrow, even in
adults.

--We now know that the B- and T-cell development that predominates--2
during late fetal life and after birth is distinct from lymphocyte (occurs as waves)
development that take place earlier in fetal ontogeny. --!

---In early fetal life, the lymphocyte development originates from stem cells found
in the fetal liver and in even more primitive hematopoietic tissues in the
developing embryo.

-- B and T cells that develop from these early fetal progenitors generally populate
mucosal and epithelial tissues and function in innate immune responses. In the
adult, these subsets of lymphocytes are minority populations in secondary
lymphoid tissues.