Humoral
And Cellular Immunity
Humoral (antibody-mediated) immunity
Antibodies (also known as immunoglobulins, Ig) are produced by terminally
differentiated B cells, known as plasma cells. Antibody responses to protein
antigens require T cell help (T-dependent antigens). The production of
antibodies to carbohydrate antigens (e.g. the polysaccharide capsule
surrounding some bacteria) occurs in the marginal zone of the spleen, and does not
require T cell help (T-independent responses). In transplantation, T-dependent
responses are the most important and occur via the following steps. (1.) B
cells recognise antigen via their surface B cell receptor (BCR), a
membrane-bound IgM antibody molecule.
BCR-bound antigen is internalised,
processed and presented on the surface of the B cell in the groove of class II
major histocompatibility (MHC) molecules, also known as human leucocyte
antigens (HLA). The antigen is presented to a ‘cognate’ T cell, i.e. one that
has a cell surface receptor (the T cell receptor [TCR]), which recognises the
same antigen in the context of that particular MHC molecule. As the B cell
presents antigen, it also provides a co-stimulatory signal to the T cell. This
occurs by the interaction of pairs of molecules found on the surface of B and T
cells (e.g. CD86 on B cells and CD28 on T cells). The T cell in turn provides
help to the B cell, including the provision of the cytokine interleukin (IL)-4. (2.) Following the receipt of T
cell help, some B cells proliferate and
form short-lived plasmablasts, which produce large quantities of low-affinity
antibody. (3.) Other B cells
move into B cell follicles in lymphoid tissue and subsequently undergo class
switching (they begin to express IgG or IgE rather than IgM) and affinity
maturation in the germinal centre. Affinity maturation involves the
introduction of mutations into the genes encoding the variable
(antigen-binding) region of the antibody (somatic hypermutation) to generate a
BCR with higher affinity for antigen. (4.)
Following affinity maturation in the germinal centre, some B cells become
‘memory’ B cells (characterised by surface expression of CD27). They
continually circulate through the secondary lymphoid organs and if the
individual is re-challenged with an antigen, these memory B cells obtain cognate
T cell help and rapidly proliferate to produce large quantities of low-affinity
antibody. Other germinal centre B cells form short-lived plasmablasts,
producing a temporary burst of antibody. A minority of plasma cells migrate
from the spleen and lymph nodes to niches within bone marrow. (5.) Bone
marrow plasma cells are long-lived and reside in their niches for prolonged
periods (probably decades or even the entire lifespan of the human). These
plasma cells do not proliferate (and are therefore difficult to target
therapeutically), but exist as ‘protein factories’ producing serum IgG.
Antibodies (or immunoglobulins) are comprised of a heavy chain and a
light chain, and the former determines the antibody class, for example, IgG
antibodies have a γ heavy chain. Immunoglobulins have a variable
antigen-binding F(ab)2 region and an Fc region responsible for mediating many
effector functions of antibody via complement activation and Fc receptor
binding. Antibodies mediate their effector function by directly neutralising
pathogen-related toxins, opsonising pathogens for uptake by Fc receptors or
flagging cells for antibody-dependent cellular cytotoxicity (ADCC).
Cellular immunity
The effector function of the cellular immune response is principally
mediated by cytotoxic (CD8) T cells. As their name suggests, they are
professional cell killers that can poison cells (by secretion of granzyme),
punch holes in the cell membrane (using perforin) or induce the cell to commit
suicide (apoptosis) via the Fas-FasL pathway. CD8 T cells have TCRs that
recognise peptides processed from intracellular proteins (e.g. viral proteins)
and presented on the surface in the groove of MHC class I molecules. In
addition, cytokine help for CD8 T cells is provided by CD4 T cells, in the form
of IL-2. In order for CD4 T cells to be activated, they must have antigen
presented to them on MHC class II molecules by APCs (see Chapter 8),
which is recognised by the TCR (signal 1). A co-stimulatory signal is also required
(signal 2). APCs up-regulate expression of co-stimulatory molecules when they
detect a danger signal, for example a pathogen-associated molecular pattern
(PAMP). If signal 1 is received in the absence of signal 2, then the T cell
will become anergic or will undergo apoptosis. This acts as a means of guarding
against activating CD4 T cells against self-antigens. If both signals 1 and 2
are received then the CD4 T cell will up-regulate expression of CD25 (the
α-chain of the IL2 receptor [IL2R]), converting it from its low-affinity
dimeric form to a high-affinity trimeric form, which avidly binds IL2 providing
a further activation signal to the T cell (signal 3). The CD4 T cell will then
proliferate, synthesise IL-2 (stimulating self-activation and the activation of
CD8 T cells) and begin to orchestrate a powerful adaptive immune response.
Following this process, some CD4 and CD8 T cells become memory cells, and can
be more readily activated following subsequent exposure to the same antigen.
CD4 T cells can also provide help to activate macrophages through the
production of cytokines such as interferon-γ (IFN- γ). In response to IFN- γ,
macrophages (and dendritic cells) produce IL12, which further drives the
production of IFN- γ by T cells. Helper T cells programmed or polarised to
produce IL-2 and IFN- γ are known as Th1 cells, and this lineage is
characterised by the expression of the transcription factor Tbet. Those
producing IL4 and promoting humoral immunity are known as Th2 cells, and are
characterised by expression of GATA3. More recently, CD4 T cells that produce
IL17 have been described (Th17 cells). IL17 plays a pathogenic role in a number
of autoimmune diseases, although its role in transplant rejection is less
clear.
Regulatory immune cells
Some T and B cells have the capacity to inhibit immune activation and
play an important role in limiting pathogenic autoimmune responses. Regulatory
T cells are characterised by the expression of the transcription factor foxp3
and have high surface expression of CD4 and CD25. They mediate suppression
principally through the production of transforming growth factor (TGF)-β and
IL10. Regulatory B cells are CD19+, CD24 high and CD38 high, and they mediate
immune suppression by production of IL-10. These cells may potentially play an
important role in the induction of transplant
tolerance.
