Key Notes
The TCR for antigen is only found on the T cell membrane and is composed of two polypeptide chains, αand β. Each of these glycoproteins is made up of constant and variable regions, like those of Igs, and together the αand βchain variable regions constitute the antigen-binding site. Some T cells, whose function is not clear, express a TCR consisting of γand δchains. These cells have some of the characteristics of αβ T cells, but have a broader specificity for unconventional antigens such as heat shock proteins and phospholipids.
The T cell receptor complex consists of the antigen receptor, the αβor γδ dimer, plus CD3, a signaling complex composed of γ, δ and εchains (and a separate signaling moiety made up of two ζchains). CD4 on T cells binds to the nonpolymorphic region of MHC class II on APCs restricting Th cells to recognizing only peptides presented on MHC class II molecules. CD8 on cytolytic T cells binds the nonpolymorphic region of MHC class I, restricting killing to cells presenting peptide in MHC class I.
Two classes (Class I and II) of polymorphic MHC genes encode human leukocyte antigens (HLA) that can bind peptides and are thus critical to antigen presentation. Class I genes(HLA-A, -B, -C) encode a polymorphic heavy chain which combines with β2-microglobulin and is expressed on the surfaces of all nucleated cells. The heavy chain has a ‘binding groove’ for peptides to be recognized by T cells. Class II genes(HLA-D) encode molecules (HLA-DP, -DR, and -DQ) composed of two dissimilar polymorphic polypeptide chains (an α and βchain), both of which contribute to the peptide-binding groove.
The polymorphic regions of MHC class I and class II are the peptide-binding domains of these molecules and bind peptides ranging from 8–10 and 10–20 amino acid residues, respectively. Anchor residues on the peptides bind to residues in the class I and II grooves and vary for different MHC alleles. This forms at least one basis for the genetic control of immune responses.
MHC class II molecules are expressed on B cells, dendritic cells and macrophages, efficient APCs for the activation of CD4+helper T cells. MHC class I molecules are expressed on all nucleated cells, permitting cytolytic T cells to recognize cells infected with intracellular pathogens. Cytokines modulate the expression of MHC class I and/or II molecules.
Peptides that bind to class I MHC molecules are derived from viruses that have infected host cells. Peptides generated in the cytosol (e.g. from viral proteins) become associated with MHC class I molecules which move to the surface (endogeneous pathway) and are recognized by CD8+cytotoxic T lymphocytes (CTL).
T cell receptor (TCR) for antigen
The T cell receptor complex
Structure of MHC molecules
Nature of MHC binding peptide
Cellular distribution of MHC molecules
Class I processing pathways
Some pathogens replicate in cellular vesicles of macrophages, others are endocytosed from the environment into endocytic vesicles (exogenous pathway).
In both cases peptides from proteins associated with these microbes are primarily presented on MHC class II molecules to CD4+helper T cells.
Related topics
There is as much diversity of TCR as of Ig receptors, but unlike the B cell anti- gen receptor (Ig), the TCR for antigen is only found on the T cell membrane and not in the serum or other body fluids. Two different groups of T cells can be defined based on their use of either αand β or γ and δ chains for their TCRs.
Both develop in the thymus.
Alpha/beta (ab)T cells
αβ T cells are the ‘conventional’ T cells that undergo positive and negative selection in the thymus (Topic F3) and make up the majority of human periph- eral T cells. These αβ T cells complete their functional maturation in the second- ary lymphoid tissues and provide protection against invading microbes. Some T cells reside, at least temporarily, in T-cell-dependent areas of tissues. These cells function to control intracellular microbes and to provide help for B cell (anti- body) responses. Two different kinds of αβT cells are involved in these func- tions, T helper (Th) cells and T cytotoxic (Tc) cells.
The TCR of these cells is composed of two polypeptide chains, αand β, which have molecular weights of 50 and 39 kDa, respectively. Each of these glycoproteins is made up of constant and variable regions like those of Ig and together the αand βvariable regions constitute a T cell antigen-binding site (Fig. 1). However, as pre- viously indicated, TCR, unlike antibodies, do not recognize native antigen, but can only bind processed antigen presented in MHC molecules. The genes coding for TCR polypeptide chains are members of the Ig super family.
Gamma/delta (gd)T cells
γδ T cells are similar in morphology to NK cells containing intracellular gran- ules (Topic C1) and represent a subpopulation of thymocytes and a small group of peripheral T cells. They express a TCR consisting of γand δ chains with V T cell receptor
(TCR) for antigen
Antigens (A4) Lymphocytes (C1)
Shaping the T cell repertoire (F3) Transplantation antigens (M2)
118 Section F – The T cell response – cell mediated immunity
Alpha chain Beta chain
Variable region
Constant region
lipid layer
S S
S S
S S
S S
S S
Fig. 1. T cell antigen receptor abdimer.
Class II processing pathways
and C regions that are similar to the αβTCR. Unlike ‘conventional’ αβT cells that have highly specific recognition structures, these cells appear to have a broader specificity for recognition of unconventional antigens such as heat shock proteins and phospholipids and do not recognize them in association with MHC molecules. However, since these cells are produced in the thymus, have a T cell receptor and express T-cell-associated molecules they are believed to represent a transition state between the innate and adaptive immunity.
Although the function of these γδ-TCR-expressing T cells is not well under- stood, they are often found at epithelial surfaces and may control microbes at this location through cytotoxic activity and cytokine production.
The T cell receptor complex consists of the antigen receptor, the αβor γδdimer, associated with several other polypeptides important in T cell signaling and recognition. In particular, the TCR is associated with CD3, a signaling complex which is itself composed of several polypeptides including γ, δand ε. ζchains are also part of the signaling complex (Fig. 2). Two other molecules, CD4 and CD8, on T cells also play a role in T cell recognition of antigen. CD4 binds to the non-polymorphic region of MHC class II and restricts Th cells to recogniz- ing only peptides presented on MHC class II molecules (Fig. 3). Similarly, CD8 The T cell
receptor complex
F2 – T cell recognition of antigen 119
ε δ γ ε
α chain β chain TCR
CD3 CD3
}
} }
ξξ
T cell (helper)
APC
CD4
T cell (cytotoxic)
Virus infected cell
CD8 β2 microglobulin
MHC class I MHC class II
PEPTIDE
ξξ ξξ
Fig. 3. CD8 and CD4 recognition of MHC class I and class II molecules, respectively. CD4 on T helper cells bind to the nonpolymorphic region of MHC class II; CD8 on cytolytic T cells binds the nonpolymorphic region of MHC class I.
Fig. 2. The TCR complex consists of the antigen receptor, the abor gddimer, associated with several other polypeptides involved in T cell signalling. The signalling complex is composed of CD3-g, dand epolypeptide chains and a separate homodimer of xchains.
on cytolytic T cells binds the nonpolymorphic region of MHC class I, restricting these killer T cells to recognize only cells presenting peptide in MHC class I molecules.
Although molecules coded for by the MHC were originally identified based on their role in transplant rejection, they actually evolved to present foreign antigens to T cells. Two classes (class I and II) of MHC genes, closely linked on chromosome 6 in humans, code for human leukocyte antigens (HLA) which are the molecules critical to antigen presentation. There are many alternative forms of genes for each subregion of the MHC. This high degree of polymorphism in class I MHC and class II MHC molecules is notdue to generation of diversity within the individual (as is the case for Ig molecules) but rather to the many alternative forms or alleles of MHC that exist in the species (Topic M2). These different alleles are not inherited entirely randomly as there is a variable distri- bution of determinants among different ethnic groups. Moreover, these alleles are inherited in groups. The combination of the encoded alleles at each of the loci within the MHC on the same chromosome is referred to as the haplotype (for haploid, as opposed to diploid). Since genes within the MHC are closely linked, haplotypes are usually inherited intact.
Class I genes (HLA-A, -B, -C)
Class I genes encode class I molecules that are expressed on the surfaces of all nucleated cells as two polypeptide chains. Only the H-chain is coded by the MHC, and contains regions of sequence variability that are the result of the many allelic forms of MHC class I molecules in the population. This accounts for the more than 35 million HLA phenotypes (Topic M2). The L-chain, β2- microglobulin (different from κ and λ Ig L-chains), shows no polymorphism and is coded for on chromosome 15. The H-chain of these molecules has a region that forms a ‘binding groove’ for peptides, such that when the class I molecule is synthesized it is able to interact with and bind certain kinds of peptides. Only the H-chain is involved in this binding, with β2-microglobulin stabilizing the molecule and permitting it to be displayed on the cell surface (Fig. 4).
Class II genes (HLA-D)
Class II genes encode structural glycoproteins found on B cells, macrophages and dendritic cells, as well as sperm, and vascular endothelial cells. This Structure of
MHC molecules
120 Section F – The T cell response – cell mediated immunity
Cell
Class I Class II
Cell (APC) β-2 microglobulin
Peptide in binding groove of class II molecule Peptide in
binding groove of class I heavy chain
α-chain α-chain β-chain
Fig. 4. MHC class I and class II molecules binding peptide.
HLA-D region can be subdivided into sets of genes which encode different HLA-DP, -DR, and -DQ class II molecules. Class II molecules are composed of two dissimilar polypeptide chains (i.e. an α and β chain heterodimer). Both chains are encoded by the MHC and β2-microglobulin is notinvolved. As with class I MHC molecules, class II MHC molecules are polymorphic due to their many different allelic forms (Topic M2) and are also able to bind peptides. In this case both the αand βchains of the class II molecule contribute to the bind- ing groove (Fig. 4).
The peptide-binding domains of MHC class I and class II molecules are differ- ent for each allelic form of the MHC molecules. That is, there are particular amino acid residues in the ‘binding groove’ that vary from one allelic form to another and thus from individual to individual. Polymorphic residues within the peptide-binding pocket of each of the molecules make contact with the anti- genic peptide. The peptides that are bound by MHC class I and class II mole- cules are short, ranging from 8–10 amino acid residues (for MHC class I) to 10–20 amino acid residues (for MHC class II). The sites on the peptides that fasten the peptide to the MHC molecule are the anchor residues(Topic A4 Fig.
2). The peptide residues in the MHC-binding groove are the same for each allelic form of the MHC molecule. Therefore, each allelic form of MHC molecule is only able to bind peptides bearing specific anchor residues. Thus, depending on the MHC molecules that are inherited, a person might not be able to bind specific peptides from e.g. a virus. If the person’s MHC molecules cannot bind the peptides generated from a specific virus, then they will be unable to mount a CD8 response to that virus. This forms at least one basis for the genetic control of immune responses. That is, the MHC molecules inherited by an individual ultimately determine to which peptides that individual can elicit T-cell-mediated immune responses, and at the population level, the poly- morphism increases the chances of survival of at least some individuals.
MHC class I and MHC class II molecules have a distinct distribution on cells (Table 1) that directly reflects the different effector functions that those cells play. Furthermore, under some conditions (e.g. cytokine activation) the expres- sion of MHC class I and/or II molecules may be induced or enhanced (e.g.
activated T cells become class II positive). Cells that express MHC class II mole- cules (B cells, dendritic cells, macrophages) are efficient antigen-presenting cells for the activation of CD4+helper T cells. In contrast, MHC class I molecules are expressed on virtually all cells in humans except for RBC. The expression of Cellular
distribution of MHC molecules Nature of MHC binding peptide
F2 – T cell recognition of antigen 121
Table 1. Expression of MHC class I and II molecules
Tissue MHC class I MHC class II
T cells +++ –
B cells +++ +++
Macrophages +++ ++
Dendritic cells +++ +++
Neutrophils +++ –
Hepatocytes + –
Kidney ++ –
Brain + –
Red blood cells – –
MHC class I molecules on all nucleated cells permits the immune system to survey these cells for infection by intracellular pathogens and allows their destruction via class I-restricted CTLs. It is interesting to note that the absence of class I MHC molecules on RBC may allow the unchecked growth of Plasmodium, the agent responsible for malaria.
To a large extent, fragments of peptides that bind to class I MHC molecules are derived from viruses that have infected host cells (Fig. 5). Degraded viral proteins (peptides of 8–10 aa) are transported into the endoplasmic reticulum by specific transporter proteins (transporters associated with antigen processing; TAP). In this intracellular compartment linear peptides bind to class I MHC molecules (endoge- neous pathway). The class I MHC–peptide complex is then exported to the cell sur- face. In general, peptides generated in the cytoplasm, i.e. the cytosol (as would be the case for cytosolic microbes), become associated with MHC class I molecules that move to the surface and can be recognized by cytotoxic T lymphocytes (CTL), which are distinguished by expression of CD8 (Table 2).
While viruses and some bacteria replicate in the cytosol, several types of pathogens including mycobacteria and Leishmania replicate in cellular vesicles of macrophages. In addition, pathogens can be endocytosed from the environ- ment into endocytic vesicles (Table 2). Thus, both pathogens in cellular vesicles and pathogens and antigens that come from outside the cell (exogenous pathway) are primarily presented on MHC class II molecules. Class II MHC molecules are present in the endocytic vesicles of macrophages, B cells and dendritic cells that present antigen to CD4+helper T cells. Upon fusion with the endocytic vesicles, class II MHC molecules become loaded with linear peptides of 10–20 aa, and the class II–MHC peptide complex is transported to the cell surface where it can be recognized by CD4+ T cells (Fig. 5). CD4 T cells also assist in the destruction Class II
processing pathways Class I processing pathways
122 Section F – The T cell response – cell mediated immunity
Endoplasmic reticulum (ER) Cytosol
Cell surface
MHC class I
MHC class II Virus
Endosome
Transport Fusion Acidified
vesicle proteases
Viral infection
Viral peptides
Transport of peptides into the ER by
‘TAP’
Pathogen/protein
MHC Class I (CD8 recognition) MHC Class II (CD4 recognition)
Fig. 5. Comparison of the pathways used to generate peptides that bind to MHC class I and class II molecules.
of parasites in vesicular compartments, e.g. mycobacteria, by activating the cells that harbor these pathogens to kill them. For extracellular parasites, CD4 T cells can activate macrophages to endocytose and destroy the pathogens, as well as instruct B cells to produce antibody to opsonize the pathogens. There are two subsets of CD4+cells potentially involved in these responses (Topic F5).
F2 – T cell recognition of antigen 123
Table 2. MHC class I and II processing pathways
Cytosolic Intracellular Extracellular
pathogens pathogens pathogens
Degraded in: Cytosol Acidic vesicles Acidic vesicles Peptides presented by: Class I MHC Class II MHC Class II MHC Peptides presented to: CD8 T cells CD4 T cells CD4 T cells
(cytotoxic) (helper) (helper)
Effect on APC: Cell death Activation of Activation of B macrophages to kill cells to secrete Ig, intracellular parasites to eliminate
extracellular pathogens/toxins
Section F – The T cell response – cell-mediated immunity