Download T cell-mediated immunity The nature of antigen recognition by T

T cell-mediated immunity
The nature of antigen recognition by T lymphocytes
 The B cell antigen receptor is surface immunoglobulin, the secreted form of
which is antibody. The T cell receptor for antigen (TCR) is composed of two
polypeptide chains referred to as the TCR  and  chains. There is no
secreted form of the TCR, i.e. T cells do not produce an equivalent to
antibodies secreted by B cells.

Both the  and  chains of the TCR are anchored in the surface membrane.
Each chain is about the same size as an immunoglobulin light chain. Indeed,
the TCR  and  chains are each composed of two immunoglobulin-like
domains with strong structural homologies with immunoglobulin domains: for
this reason, the TCR is said to be a member of the immunoglobulin
superfamily. In each chain, the domain proximal to the membrane is
constant in structure between T cells (C and C), whereas the domains distal
to the membrane are variable in structure between T cells (V  and V) and
form a single antigen combining site: thus the TCR has one antigen combining
site, whereas sIg on B cells has two.

Whereas the main function of B cells is to produce antibodies that directly
target microbes, the job of T cells is to do things to other cells of the body in
the context of an immune response. Some T cells, called T helper (Th) cells,
help other cells of the immune system to fulfil their functions – eg. Th cells
activate B cells to produce antibodies, and stimulate the phagocytic and killing
activity of macrophages. Other T cells, called T cytotoxic (Tc) cells, kill tissue
cells that have become infected by microbes.

B cells are able to bind microbial antigens in their natural (native) form
directly to their surface Igs, leading to the production of antibodies that are
specific for the same antigens. By contrast, the TCR of T cells cannot interact
directly with microbes and their antigens, but bind only to fragments of
antigenic proteins (i.e. antigen peptides) associated with tissue cells, thereby
targeting the T cells to mediate their helper or cytotoxic activities against
these cells. Cells that present antigen peptides that T cells can bind to are
termed antigen presenting cells (APC). In the cytoplasm of APCs, microbial
proteins are broken down into peptides (termed antigen processing); some of
these antigen peptides than associate with specialised peptide-binding
proteins that hold the peptides on the APC surface where they are available to
interact with the TCR of T cells. In humans, the antigen-binding proteins are
called HLA proteins (Human Leucocyte Antigens) – more generally, in humans
and other species, they are termed MHC proteins (proteins of the Major
Histocompatibility Complex).
Antigen presentation and processing
 There are two types of HLA proteins, termed class I and class II. HLA class I
protein consists of a large  chain non-covalently associated with a
polypeptide called  2-microglobulin ( 2M). The 3 domain and  2M that are
proximal to the cell surface have amino acid sequence and structural
homologies with the domains of immunoglobulins, and so HLA proteins are
members of the immunoglobulin superfamily. The 1 and 2 domains of the
HLA class I  chain form a cleft or groove on the surface of the protein distal
to the cell surface membrane that holds the antigen peptide so that it is
available for interaction with a TCR.

HLA class II protein consists two similarly sized polypeptide chains called the
class II  and  chains. Each chain has an immunoglobulin-like domain
proximal to the cell surface membrane ( 2 and 2 domains), while the 1
and  1 domains distal to the cell surface membrane jointly form a peptide
binding cleft that holds an antigen peptide for recognition by TCR.

HLA class I proteins present antigen peptides mainly to Tc cells whereas HLA
class II proteins present antigen peptides mainly to Th cells. This is because
Tc cells express a protein called CD8 that interacts with the 3 domain of HLA
class I when the TCR binds to the antigen peptide held in the antigen binding
cleft, but CD8 does not bind to HLA class II. By contrast, Th cells express a
protein called CD4 that interacts with the  2 domain of HLA class II, but does
not interact with HLA class I. The CD8-class I and CD4-class II interactions
strengthen the overall binding between APCs and T cells, and provide
additional activation signals that synergise with those delivered to the T cells
via the TCR. CD4 and CD8 are both members of the Ig superfamily.

Processing of antigen for presentation by HLA class I: endogenous protein
antigens present in the cytoplasm are degraded in an enzyme complex called
a proteasome; some of the peptides generated are transferred to the
endoplasmic reticulum via peptide transporter proteins; peptides of
appropriate length (eight or nine amino acids) and amino acid sequence
associate with newly synthesized HLA class I molecules; the peptide–HLA
class I complexes are transported to the cell surface where they are available
for recognition by Tc cells expressing CD8.

Processing of antigen for presentation by HLA class II: endocytosis of
exogenous protein antigen leads to its internalization into a vesicle; enzymes
entering the vesicle degrade the antigen; newly synthesized HLA class II
molecules in the endoplasmic reticulum associate with the invariant chain
(that prevents peptide binding) and are transported to the vesicle; the
invariant chain is degraded in the vesicle and antigen peptides of the
appropriate length and amino acid sequence associate with the HLA class II
molecules; the peptide–HLA class II complexes are transported to the cell
surface where they are available for recognition by Th cells expressing CD4.

Activated Tc recognise antigen peptides bound to HLA class I proteins on the
surface of infected target cells (eg. containing replicating viruses), thereby
directing the Tc to kill infected rather than normal cells. Activated Th cells
recognise antigen peptides bound to HLA class II proteins on the surface of
macrophages or B cells that have bound and internalised microbial antigens.
This directs the Th cells to help the macrophages become more aggressive
phagocytes, and the B cells to produce antibodies.

Most cells of the body express HLA class I molecules, which is consistent with
the fact that different microbes infect different cell types, so any cell can
become a target for killing by Tc cells if it is infected. Expression of HLA class
II proteins, by contrast, is mainly restricted to cells of the immune system
(eg. macrophages and B cells), which are the cells that require activation
signals from Th cells.

The APC that act as the primary stimulators of naïve resting T cells are
dendritic cells (DC). These are found in most tissues of the body where they
capture antigens and transport them to nearby lymphoid tissues (eg. lymph
nodes), where the antigens are presented to the available T cells. In this
way, the dendritic cells are able to pick out the small proportion of T cells,
from the millions present in lymphoid tissue, that specifically recognise the
antigen peptides presented on the surface of the DC. Peptides derived from
antigen processing within the DC can be bound to either HLA class II or class
I molecules, so DC are able to activate both Th and Tc cells. In order to
achieve these functions, DC are first of all activated themselves when
microbial molecules bind to their pattern recognition receptors (particularly
Toll-like receptors), inducing the DC to produce cytokines that activate T cells
and to express co-stimulatory proteins (eg. CD80 and CD86) that are
necessary for T cell activation.
Recommended reading:
Todd I, Spickett G (2005) Lecture Notes: Immunology. 5th edition. Blackwell
Publishing. Chapters 2, 3 and 4. OR
Todd I, Spickett G (April 2010) Lecture Notes: Immunology. 6th edition.
Wiley/Blackwell. Chapters 2, 3 and 4.