Understanding the Function of Lymphocyte Antigen Receptors in Adaptive Immunity
The innate immune system is commonly able to containing and
eradicating microbial invaders, however some microbes have advanced
methods to subvert or evade innate immunity. The subsequent line of host
protection is the adaptive immune system, which consists
of lymphocytes (additionally referred to as lymphoid cells) and their secreted
elements (see Desk 57–1).
A vital property of adaptive immunity is that the immune
response is particularly tailor-made in opposition to completely different microbes.
That is achieved by first producing an infinite variety of
numerous lymphocytes, every with a singular antigen specificity.
Earlier than they see their antigen, these lymphocytes are referred to as naïve
(Determine 59–1). How these cells operate is intently linked to how
they develop from stem cells, so so as to perceive how
lymphocytes can assist host protection or may cause illness, it’s first
essential to grasp lymphocyte improvement.
ORIGIN OF LYMPHOID CELLS
As described in Chapter 58, all white and crimson blood cells
originate from stem cells within the fetal liver and yolk sac throughout
embryonic life and within the bone marrow after beginning (see Determine
58–1). The frequent lymphoid progenitor is a sort of stem cell
that offers rise to lymphocytes of the adaptive immune system,
together with B cells and T cells. The frequent lymphoid pro-
genitor can also be the supply of innate lymphocytes, comparable to pure
killer (NK) cells. The method by which frequent lymphoid
progenitors become lymphocytes is determined by cytokines,
and mutations within the genes encoding the receptors of those cyto-
kines are sometimes the reason for extreme mixed immunodeficiency,
an entire absence of mature lymphocytes (see Chapter 68).
The ratio of T cells to B cells is roughly 3:1. Determine 59–1
describes the origin of B cells and two of the primary kinds of
T cells. Typically T cells are named by markers we will detect on
their cell floor, referred to as “cluster of differentiation” (CD)
markers: helper T cells are CD4-positive (CD4+), whereas cyto-
poisonous T cells are CD8-positive (CD8+). Desk 59–1 compares
varied essential options of B cells and T cells. These options
will likely be mentioned intimately on this and later chapters.
LYMPHOCYTE RECEPTOR DIVERSITY
All vertebrates produce enormously numerous swimming pools of antigen
receptors; in people, this pool is estimated to comprise 100 million
completely different specificities, defending us from hundreds of thousands of potential
pathogens. How can we accomplish this with a genome that solely
accommodates roughly 20,000 genes? The answer is that dur-
ing their improvement, T and B lymphocytes do one thing
extraordinarily unconventional. They change on a program of DNA
rearrangement, chopping their DNA, eradicating items, and shuf-
fling different items, to kind completely new coding sequences of their
antigen receptor genes. The 2 most essential enzymes on this
course of are recombinases, referred to as RAG-1 and RAG-2 (recombi-
nation-activating genes). The RAG genes have been present in our
first vertebrate ancestors from 500 million years in the past.
This DNA rearrangement is completely essential for our
adaptive immune system; mutations in these RAG genes halt
the event of lymphocytes and lead to extreme mixed
immunodeficiency (see Chapter 68). Nonetheless, DNA rearrange-
ment can also be dangerous. The RAG proteins are speculated to work solely
in particular areas (i.e., within the immunoglobulin and T cell
B CELLS
B cells carry out two essential capabilities: (1) they differentiate
into plasma cells that produce antibodies (additionally referred to as immuno-
globulins) and (2) they’ll grow to be long-lived reminiscence B cells
that may quickly reply to a reinfection. The immunoglobulin
on the B-cell floor is its antigen receptor (B-cell receptor or
BCR) and the power of a B-cell precursor to make this antigen
receptor determines whether or not it’s allowed to develop right into a mature
B cell.
B-cell precursors first come up from stem cells within the fetal liver,
however by the point of beginning, these stem cells migrate to the bone
marrow, which is their fundamental location throughout childhood and
grownup life. In contrast to T cells, B cells don’t require the thymus for
maturation. The maturation of B cells has two phases: the primary
is the antigen-independent part, which consists of stem cells,
pre-B cells, and B cells, and it’s throughout this part that the
B cell recombines its immunoglobulin genes to make a singular
antigen receptor. For pre-B cells to distinguish into B cells, a
purposeful immunoglobulin should be current on the cell floor.
A protein referred to as Bruton’s tyrosine kinase (BTK) detects this
immunoglobulin and indicators to the cell to proceed to divide
and differentiate. A mutation within the gene encoding this protein
causes X-linked agammaglobulinemia, a situation wherein
cells can’t progress to the pre-B cell stage and no antibodies
are made (see Chapter 68).
Throughout the second part, which is the antigen-dependent
part, mature B cells with purposeful antigen receptors inter-
act with antigens. This part will likely be lined in additional element in
Chapter 61.
The immunoglobulin (Ig), or BCR, of a mature B cell is an
IgM molecule with an extra area on the finish of its heavy
chain that tethers it to the B-cell floor. Roughly 109
B
cells are produced every day, however solely a small fraction of those
make it from the bone marrow into the circulation, and except
they’re activated via their antigen receptors, circulating B
cells have a brief life span (i.e., days or perhaps weeks). On this chapter,
we are going to discover the construction and variety of BCRs, and in
Chapter 61, we are going to describe how these antigen receptors trigger
activation of B cells and the way the ensuing antibodies present
host protection.
Antibody Construction
Antibodies are glycoproteins made up of sunshine (L) and heavy (H)
polypeptide chains. The phrases mild and heavy discuss with molecular
weight; mild chains have a molecular weight of about 25,000,
whereas heavy chains have a molecular weight of fifty,000 to 70,000.
The only antibody molecule has a Y form (Determine 59–2) and
consists of 4 polypeptide chains: two an identical H chains and
two an identical L chains. In different phrases, though you obtained
copies of H and L chain genes from every of your dad and mom, every B
cell in the end synthesizes solely one of many H chain genes and one
of the L chain genes to make use of to kind an antibody, and subsequently, all
of the following antibodies from that B cell and its progeny use
the identical H and L chains. Desk 59-2 is a abstract of the proper-
ties of the human lymphocyte antigen receptors.
One finish of the Y consists of two an identical items that
bind the antigen, and subsequently, that is referred to as the antigen-
binding fragment (or Fab). The Fab contains the variable
area of the L chain (VL) and the variable area of the H chain
(VH), in addition to the fixed area of the L chain (CL) and the
first fixed area of the H chains (CH1). The parts of
the L and H chains that really bind the antigen are solely 5 to
10 amino acids lengthy, every composed of three extraordinarily vari-
ready (hypervariable) amino acid sequences. Antigen–antibody
binding includes electrostatic and van der Waals’ forces and
hydrogen and hydrophobic bonds fairly than covalent bonds.
The outstanding specificity of antibodies is because of these hyper-
variable areas.
The opposite finish of the Y is a single stalk, the place the H chains
come collectively, and it’s manufactured from the remaining three or 4
fixed areas of every of the H chains (CH2, and many others.). That is
referred to as the fixed or “crystallizable” fragment (or Fc). You
would possibly assume that the Fab is an important a part of the
antibody as a result of it binds the antigen, however the Fc is required to
connect the antibody to host cells (e.g., through Fc receptors) or to
complement (on the CH2 area). The Fc can also be the area that
is used to fuse IgM and IgA collectively into bigger “multimers.” It
can also be essential for transport of IgA throughout epithelial obstacles
and transport of IgG from mom to fetus via the placenta.
There are 5 lessons of antibodies: IgM, IgD, IgG, IgE, and
IgA. Every class has structural variations that make it distinctive.
For instance, IgG and IgA have three CH domains, whereas
IgM and IgE have 4. The structural variations between the
antibody lessons translate into essential purposeful variations.
Mature naïve B cells begin out making solely IgM and IgD however
later “change” to creating the opposite lessons. We are going to talk about the
completely different antibody capabilities and the way the B cells class-switch in
Chapter 61.
L chains might be of two sorts, κ (kappa) or λ (lambda), which
differ of their fixed areas. Both kind can pair with H
chains in all lessons of immunoglobulins (IgG, IgM, and many others.), however
as soon as a B cell chooses to make use of κ or λ, it shuts off the opposite L chain
gene, in order that all the immunoglobulin from anyone B cell con-
tains just one kind of L chain. In people, the ratio of immu-
noglobulins containing κ chains to these containing λ chains is
roughly 2:1, and a price dramatically completely different generally is a
signal of a monoclonal immunoglobulin-producing malignancy
comparable to a number of myeloma.
H chains are distinct for every of the 5 immunoglobulin
lessons and are designated γ (gamma), α (alpha), μ (mu), ε
(epsilon), and δ (delta). The VH hypervariable area of the H
chain joins with VL in binding antigen; the alternative areas of
the VH chains kind the Fc fragment, which determines which
class the antibody is and, subsequently, what its biologic actions
will likely be (see Chapter 61).
Antibody Genes
As described earlier, every antibody consists of 4 immu-
noglobulin chains (two mild chains and two heavy chains).
There are two mild chain gene clusters, one encoding kappa
mild chain (κL), on human chromosome 2, and one encoding
lambda mild chain (λL), on chromosome 22. All heavy chain
genes (μH, δH, γH, εH, and αH) are collectively in a cluster on
chromosome 14. The heavy chains and lightweight chains are assem-
bled after recombining gene segments inside their respec-
tive gene clusters, a course of that’s directed by recombinase
enzymes (RAG1 and RAG2). A schematic diagram of gene
recombination is proven in Determine 59–3.
First, the VH and VL genes are recombined. Every cluster
accommodates dozens of various V gene segments extensively separated
from the D (variety, seen solely in H chains), J (becoming a member of), and C
gene segments. The VH area of every heavy chain is encoded
by three gene segments (V + D + J). Within the synthesis of a heavy
chain, one explicit V area (out of ~45) is translocated to lie
shut to 1 explicit D phase (out of ~23), one explicit J
phase (out of 6), and one C phase.
The VH/CH mixture is transcribed collectively on an RNA
molecule and spliced to provide an mRNA that codes for the
full heavy chain, encoded by a single V, D, and J phase
hooked up to a C phase. Why are IgM and IgD the primary antibod-
ies which can be produced? The newly assembled V + D + J gene seg-
ments are closest to the Cμ and Cδ genes! In Chapter 61, we are going to
describe how class switching results in IgG, IgE, and IgA, which
are additional downstream within the heavy chain locus.
The VL area of every L chain is encoded by two gene seg-
ments (V + J). Within the meeting of an L chain, the identical course of
happens besides that there are barely fewer attainable V segments
(~30–35 in kappa and lambda), and neither of the L chains
have D segments. Additionally, the kappa chain gene has a single Cκ,
whereas the lambda chain gene has 4 Cλ segments, one
already related to every J phase. The L chain comes from
an analogous translocation wherein a single V and J are introduced
shut collectively after which transcribed and translated with the
acceptable C phase. Word that the DNA of the unused V, D,
and J genes is discarded; as soon as a specific B cell has recombined
its mild and heavy chains, it’s dedicated to creating antibody
with just one specificity.
The H and L chains are synthesized as separate peptides
after which folded and assembled within the cytoplasm by the use of
disulfide bonds to kind H2L2 models. Lastly, an oligosaccharide
is added to the fixed area of the heavy chain, and the BCR
molecule is transported to the cell floor.
Clonal Choice
Word that the genetic recombination outlined earlier can lead
to an infinite variety of attainable mixtures. There are
roughly 1011 attainable heavy chain–mild chain combina-
tions! Antibody variety is determined by (1) a number of gene seg-
ments, (2) their rearrangement into completely different sequences, (3)
the combining of various L and H chains within the meeting of
immunoglobulin molecules, and (4) mutations. A fifth mecha-
nism referred to as junctional variety applies primarily to the anti-
physique heavy chain. Junctional variety happens by the addition
of latest nucleotides on the splice junctions between the V-D and
D-J gene segments. The ensuing antibodies have the potential
to acknowledge the three-dimensional construction of a variety of
proteins, carbohydrates, nucleic acids, and lipids.
Regardless of the big potential variety, the precise specifici-
ties represented among the many pool of circulating B cells that we
every have is considerably smaller (about 106
). Every immunologi-
cally responsive B cell bears copies of a single BCR on its floor
(initially composed of its VDJ + Cμ or Cδ, paired with a VJ +
Cκ or VJ + Cλ chain) that may react with one antigen (or intently
associated group of antigens). Even after that B cell divides, all of its
progenies, or clones, will proceed to make antibodies with the
similar antigen specificity.
There are two steps by which B-cell precursors are
“auditioned” and chosen to be obtainable to grow to be activated
antibody-producing plasma cells. Step one of B-cell clonal
choice is named optimistic choice. Pre-B cells lack floor
BCR. If a B-cell precursor fails to rearrange its immunoglobulin
gene segments and generate a purposeful BCR, it dies earlier than it
reaches the mature B-cell stage. That is referred to as optimistic choice
as a result of solely these cells that do generate a BCR are allowed
to outlive and mature. For instance, mutations within the genes
encoding the recombinase enzymes (see above) lead to a fail-
ure to generate antigen receptors and subsequently a deficiency of
lymphocytes (extreme mixed immunodeficiency). Equally,
a mutation within the gene on the X chromosome that encodes
Bruton’s tyrosine kinase (BTK), which is essential for trans-
mitting the BCR sign from the cell floor, leads to the
illness X-linked agammaglobulinemia, wherein B cells and
antibodies are absent. These sufferers are extra vulnerable to
bacterial infections of their sinuses, lungs, and gastrointestinal
tract as a result of they lack the antibodies that normally defend these
barrier surfaces (see Chapter 68).
Pre-B cells that do efficiently generate floor IgM go
via optimistic choice and progress to grow to be B cells. At
this stage, their IgM BCRs instantly encounter self-antigens.
Keep in mind that, whereas T-cell receptors can solely bind peptides
complexed with main histocompatibility advanced (MHC) pro-
teins, the BCR can doubtlessly bind to any circulating proteins,
lipids, carbohydrates, or nucleic acids. Nonetheless, as a result of this
part of improvement happens within the bone marrow fairly than in
the peripheral tissues or secondary lymphoid organs, all the
antigens that the B cell may encounter at this stage are self-
antigens. Throughout this part, referred to as unfavourable choice, if the
BCR strongly binds a self-antigen, this means excessive potential
for autoreactivity. This cell will likely be faraway from the pool of
mature B-cell clones, though it has one likelihood to flee this
destiny by a course of referred to as receptor modifying. On this course of, an
alternate VL mixture utilizing an unused mild chain allele can
substitute the earlier allele, creating a brand new IgM receptor. But when
this receptor can also be autoreactive, the B cells are both killed by
apoptosis or rendered “anergic” (their manufacturing of floor
IgM is turned off they usually grow to be nonsensitive to activation).
It’s estimated that 25% to 50% of circulating B cells have under-
gone receptor modifying. This part is named unfavourable choice
as a result of it ensures that solely B cells that don’t strongly bind
self-antigens are allowed to go away the bone marrow and, there-
fore, will likely be self-tolerant.
Class Switching
Initially, all B cells that exit the bone marrow carry IgM spe-
cific for antigen. At this stage, they could be thought-about mature,
as a result of they’ve a purposeful BCR, however naïve, as a result of they
haven’t but encountered their cognate antigen. Later, in a
course of referred to as class switching, additional gene rearrangement
permits new antibodies that use the identical VH however completely different CH
chains. (In Chapter 61, we are going to describe how activation of B
cells causes this class switching and the operate of the differ-
ent Ig lessons.) A B cell that has class switched from IgM can
by no means return.
Allelic Exclusion
A single B cell has one maternal and one paternal copy of the L
chain genes (each κ and λ) and the H chain gene. As described
earlier, B cells that acknowledge self-antigens throughout clonal selec-
tion can try “receptor modifying,” swapping within the alternate
allele, to flee apoptosis or anergy. However as soon as they’ve suc-
ceeded in exiting the bone marrow as a mature B cell, the alleles
that gave them the profitable BCR are mounted and the others are
silenced. That is referred to as allelic exclusion. All of us have a various
combination of B-cell clones expressing completely different mixtures of
paternal and maternal genes. The exact mechanism of how the
alternate alleles are turned off is unknown.
T CELLS
Like B cells, T-cell precursors derive from frequent lymphoid
progenitors. However in contrast to B cells, T-cell improvement contains
a step wherein the precursors migrate via a specialised
organ referred to as the thymus, which is why they’re abbreviated “T”
cells. Word that previous to getting into the thymus, T-cell precursors
lack antigen receptors (T-cell receptors, or TCRs) and lack the
different floor receptors that help TCR signaling. It’s throughout
passage via the thymus {that a} T-cell precursor begins to
categorical a singular TCR, and upon exiting the thymus, they’re
referred to as mature naïve T cells as a result of at this stage they’ve by no means
seen international antigens.
Word that the thymus begins to degenerate on the time of
puberty, but adults proceed to provide new T cells, suggesting
that one other website would possibly take over as soon as the thymus stops func-
tioning. However, it’s clear that the thymus is required for
regular improvement of T cells, as sufferers with a congenital
illness referred to as DiGeorge’s syndrome, who’re born and not using a
thymus, are T-cell poor and die at an early age of an infection
if they don’t seem to be handled (see Chapter 68).
T-Cell Receptor Construction
Earlier, we described BCRs as having two an identical mild chains
(lambda or kappa) and two an identical heavy chains (mu, delta,
gamma, alpha, or epsilon). TCRs have analogous chains however
solely have two chains as an alternative of 4. With uncommon exceptions,
which we are going to talk about later within the chapter, the TCR is com-
posed of a single α (alpha) chain and a single β (beta) chain
(Determine 59–4 and Desk 59-2). Every chain features a variable
area, which incorporates the hypervariable area that binds
to the peptide–MHC advanced, and a relentless area, which
attaches the α chain and β chain to one another.
The α chain and β chain are largely positioned outdoors the cell,
and they’re mounted to the cell membrane by a transmembrane
area and a brief cytoplasmic tail. The tail binds to a molecule
referred to as CD3ζ (CD3-zeta). Though it isn’t truly a part of the
antigen receptor, all T cells have CD3 proteins in affiliation
with TCR. The aim of CD3 is to transmit the TCR peptide
recognition sign from the floor to the within of the cell. That is
achieved via intracellular tyrosine kinases which can be sure to
CD3 and phosphorylate downstream second messengers.
T-Cell Receptor Genes
Throughout their passage via the thymus cortex, every double-
optimistic T-cell precursor synthesizes a unique, extremely particular
TCR. Rearrangement of variable, variety, and becoming a member of gene
segments, analogous to people who encode the B-cell immuno-
globulin receptor, accounts for the outstanding means of T cells
to acknowledge hundreds of thousands of various antigens The TCR genes are
first expressed by double-negative thymocytes, beginning with
recombination of the β chain. The TCR β chain gene is positioned
on human chromosome 7, and, just like the heavy chain genes
of immunoglobulins, it’s composed of V, D, and J segments
which can be chosen and joined at random via a course of that
requires the recombinase enzymes (RAG1 and RAG2). One
of roughly 48 Vβ segments, one in every of two Dβ segments,
and one in every of roughly 13 Jβ segments are randomly chosen
and translocated subsequent to 1 one other, adopted by translocation
near one in every of two Cβ segments. The brand new V + D + J + Cβ gene
is then transcribed, and its mRNA is spliced and translated into
a purposeful TCR β chain (Determine 59–5).
The same course of happens to recombine the TCR α chain
locus, though, like the sunshine chain genes of BCRs, the α chain
gene of the TCR has no “D” areas. The α chain is subsequently
constructed by translocating one in every of roughly 45 Vα seg-
ments (chosen at random) adjoining to one in every of roughly
50 Jα segments (additionally chosen at random), a course of that additionally
requires RAG recombination. (In contrast to the BCR mild chain
genes, which happen at two separate κ and λ loci, there’s solely
one TCR α chain gene locus, on human chromosome 14.) Subsequent,
the randomly assembled V + J segments are translocated shut
to a Cα area, and after splicing the ensuing mRNA, the TCR
α chain protein is synthesized.
As happens in B cells throughout V(D)J recombination, when the
RAG proteins recombine the DNA of the TCR α and β chain
gene loci, the unused items of DNA are completely excised,
with their ends joined collectively to kind rings. These rings of
DNA are referred to as T-cell receptor excision circles (or TRECs),
and they’re simply detected utilizing a polymerase chain response
(PCR) assay that amplifies them within the blood of individuals with
regular T-cell improvement. The truth is, many public well being depart-
ments in the US now use this assay in all newborns
as a screening take a look at for T-cell deficiency; as a result of over 70% of
T cells generate TRECs as a byproduct of their TCR, the absence
of those TRECs prompts additional testing to search out out why a child’s
T cells are failing to succeed in this stage. This take a look at is very cost-
efficient as a result of detecting T-cell deficiency on the time of beginning
permits docs to anticipate immunodeficiency and put together for
a stem cell transplant earlier than the infant has extreme infectious com-
plications (see Chapter 68).
Optimistic and Damaging Thymic Choice
Precisely analogous to B-cell improvement, every individual-cell
precursor within the thymus has a singular TCR, and even after it
divides, its progeny, or clones, will carry an an identical TCR.
Due to the big variety of Vα and Vβ segments, includ-
ing those who come from the paternal and maternal copies of
the α and β chain genes, TCR recombination can theoretically
generate 1013 completely different receptor mixtures! However we solely
have round 107
T cells in our our bodies. Earlier than they’ll exit the
thymus, T-cell precursors are subjected to thymic choice, a
rigorous two-step “audition,” analogous to that described earlier
for B cells, that generates purposeful T cells able to determine and
reply to international antigen (Determine 59–6):
(1) First, double-positive cells within the thymus cortex migrate
previous specialised thymus cells bearing MHC proteins and pre-
senting “self ”-peptides. T-cell precursors, which lack each CD4
and CD8, start to precise each proteins and recombine their
TCR genes to generate distinctive TCRs. If these “double-positive”
cells bind to the MHC proteins they encounter, they’re given
a essential survival sign via their newly shaped TCR,
main them to divide right into a inhabitants of clones (see Determine
59–6A). That is referred to as optimistic choice, as a result of solely the T-cell
precursors that do bind to MHC are chosen to outlive. (The
self-peptides introduced at this stage function a proxy for the
variety of peptides that the mature T cells will encounter when
they depart the thymus.) Cells that fail this step could make additional
makes an attempt; as a result of all cells have maternal and paternal alleles
of their TCR genes, a T cell caught at this stage can proceed
to mutate and re-audition TCR genes to make a extra appropriate
MHC-binding receptor. Nonetheless, most double-positive cells do
not survive optimistic choice. As well as, the kind of MHC that
is sure by the TCR throughout optimistic choice will decide
which kind of single-positive T cell will develop; for instance, if
the cell binds strongly to class II MHC, then it turns off CD8
expression and stays (single) CD4-positive, and the alternative
is true if the cell binds class I MHC. (That is typically referred
to as “the rule of eight” as a result of CD4-positive cells bind to class
II MHC [4 × 2 = 8], and CD8-positive cells bind to class I MHC
[8 × 1 = 8]).
Why is that this essential? For a T cell to operate, it’s essen-
tial that its TCR can work together strongly with an acceptable
MHC molecule, and optimistic choice ensures that the
T cells that ultimately exit the thymus have purposeful MHC-
binding TCRs.
(2) There’s a second choice course of that happens as dou-
ble-positive cells which have survived optimistic choice start to
transfer to the thymus medulla. As described earlier, these cells
are persevering with to contact thymus cells that show self-antigens
complexed with class I MHC or class II MHC. Any T cell that
binds too strongly to those self-presenting cells is deleted by a
means of programmed cell dying, or apoptosis (see Determine
59–6B). That is referred to as unfavourable choice, as a result of solely the
T cells that don’t strongly bind to self-peptides are allowed to
survive. For unfavourable choice to be environment friendly, the thymic cells
should show a large repertoire of self-peptides. A transcription
issue referred to as the autoimmune regulator (AIRE) directs this
array of self-peptides within the thymus.
Why is that this essential? The elimination of self-reactive cells
ensures that the naïve T cells that ultimately exit the thymus are
not particular for self-antigens, and this self-tolerance is one in every of
the important thing methods the immune system discriminates between what
is self and what’s international. Thymic choice makes use of a tightly con-
trolled sign threshold that ensures TCR binding to self MHC
is powerful (optimistic choice) and TCR binding to self antigens
is weak (unfavourable choice). Acknowledged one other approach, if TCR binding
to self MHC is simply too weak, these cells are deleted and if TCR
binding to self antigens is simply too robust, these cells are deleted.
The top result’s a naïve T cells that binds properly to self MHC
and never properly to self antigen however properly to international antigen comparable to
microbial antigens. Mutations in genes that management TCR signaling
or within the gene encoding AIRE may cause autoimmune illness
attributable to faulty thymic choice (see Chapter 66).
In abstract, optimistic and unfavourable choice take away all however
the T-cell clones that react weakly with self-peptides introduced
in complexes with MHC proteins. Word that the identical MHC
proteins which can be required for preliminary thymic choice of T-cell
precursors later grow to be the vital indicators for activating T cells
via their TCRs.
INNATE-LIKE T CELLS
Roughly 95% of the physique’s T cells are CD4-positive or
CD8-positive cells that carry αβ TCRs, as described earlier.
These cells have a extremely numerous TCR repertoire, able to
responding to a variety of potential infectious brokers. A number of
different T cells develop in an uncommon method: though they nonetheless
go via the thymus, they’ve a extremely restricted TCR
repertoire, able to responding shortly however to a slender vary
of antigens. Subsequently, as a result of these cells reply extra quickly
and are much less numerous than different T cells, they’re usually referred to as
“innate-like” (see Desk 59–2).
One kind of innate-like T cell is the pure killer T cell
(NK-T cell). As their title implies, NK-T cells share many
options with innate NK cells, together with floor receptors and
markers which can be essential for NK cell operate (see Chapter 58).
However don’t confuse the 2 cell sorts! NK-T cells should not innate
cells; they’ve an αβ T-cell receptor and require the thymus
for his or her improvement. One of the best-described NK-T cell, referred to as
the “invariant” NK-T (iNKT) cell, makes use of a extremely restricted set of
V, D, and J gene segments to create the α and β receptor chains
of its TCR (see Desk 59-2). As an alternative of recognizing peptides
complexed with MHC, the TCRs of iNKT cells acknowledge lipids
and glycolipids complexed with an alternate antigen presenta-
tion molecule referred to as CD1d. The exact function of NK-T cells is
unknown, however they could be essential in host protection in opposition to
organisms that comprise sure lipids or in responding to situ-
ations of host tissue stress wherein lipids are launched from
broken cells.
One other uncommon T cell is the mucosal-associated invari-
ant T (MAIT) cell. Like NK-T cells, MAIT cells develop within the
thymus and use a restricted set of α and β gene segments of their
TCRs, however they’re restricted to a unique antigen presentation
molecule referred to as MR1 (see Desk 59-2). Like class I MHC, MR1
is expressed on a big number of cells. Nonetheless, fairly than
solely presenting peptides, MR1 prompts MAIT cells with a large
vary of different kinds of antigens. Not all the ligands sure
by MR1 that activate MAIT cell have been recognized, however at
least a few of them are small-molecule metabolites produced by
micro organism. This will clarify why MAIT cells populate peripheral
barrier surfaces, such because the lung, gut, and liver, the place
bacterial merchandise are sometimes encountered.
Lastly, the γδ (gamma-delta) T cell is probably probably the most
uncommon innate-like T cell in that it doesn’t have an αβ TCR.
As an alternative, for causes that aren’t properly understood, on the time
when thymic T-cell precursors start to recombine the α and
β chain genes, γδ T cells as an alternative recombine the γ and δ chain
genes (positioned on human chromosomes 7 and 14, respectively).
The γ chain gene consists of V, D, and J segments (related
to the β chain), and the δ chain gene consists of V and J
segments (just like the α chain). These alternate TCR chains
then mix with CD3ζ on the cell floor. Little is understood
concerning the antigens acknowledged by γδ TCRs, however some γδ T cells
might even reply to those antigens within the absence of the standard
antigen-presenting molecules comparable to MHC, MR1, or CD1d.
Like MAIT cells, γδ T cells primarily reside in mucosal tissues,
however their activating ligands haven’t been totally characterised,
and their exact function in host protection is unclear.
