Section G – Regulation of the immune response
G2 C ENTRAL AND PERIPHERAL
‘education’ process within the thymus leads to suicide of greater than 90% of the T cells. Thus, only a small percentage of the T cells generated survive to emigrate to the peripheral tissues. These T cells are the ones capable of recognizing foreign non self peptide antigens in the context of self MHC molecules.
A similar process of negative selection occurs during B cell development in the bone marrow. As in the thymus, receptor diversity for antigen is created from rearrangement of V segement genes resulting in some B cells having membrane antibodies with self reactivity. B cell toleranceoccurs as a result of clonal deletion, through apoptosis, of immature B cells reactive to self antigens (Fig. 1). Immature B cells expressing surface IgM that react with self antigens are rendered unresponsive or anergic. Thus, only those B cells that do not react with self antigens in the bone marrow are allowed to mature and migrate to the periphery where further maturation occurs.
146 Section G – Regulation of the immune response
B Negative B
selection
†
Apoptosis
B cells binding strongly to self antigens B cells not
binding strongly to self antigens B cell
precursor
GOD
Fetal liver/bone marrow
Periphery
Fig. 1. Central tolerance: B cells. B cell precursors develop diverse antigen receptors (GOD). They undergo negative selection and the surviving cells migrate to peripheral (secondary) lymphoid organs/tissues.
Most self-reactive lymphocytes cannot all be eliminated in the primary lymphoid organs for two reasons. Firstly, many self antigens are neither present in the primary lymphoid organs nor supplied to them via the bloodstream.
Moreover, with the exception of self antigens that do not normally come into contact with the immune system (‘sequestered antigens’ such as lens proteins in the eye), most self antigens expressed as the result of differentiation of cells and tissues in the major organs of the body do not ‘pass through’ the primary lymphoid organs. Certainly, lymphocytes in the periphery do come into contact with these antigens. Secondly, different receptor specificities may be generated as the consequence of somatic mutation of the antibody genes in B cells. This occurs within the germinal centers of secondary lymphoid organs/tissues (Topics C2, D3 and E4). Unlike B cell antigen receptors, it is believed that TCRs do not normally mutate.
T cell anergy
Peripheral self-reactive T cells can be deleted or anergized. The main mecha- nism preventing autoreactivity in the periphery involves development of anergy. Naive T cells require two main signals to respond to an antigen. One comes via the TCR, the other comes from co-stimulatory molecules. The glyco- proteins B7.1 (CD80) and B7.2 (CD86) are essential co-stimulatory molecules, Peripheral
tolerance
found almost exclusively on professional antigen-presenting cells (APCs).
Interaction of these B7 molecules on APCs with CD28 on T cells is required for T cell activation (Fig. 2). Thus, in the absence of professional presentation of self antigens and engagement of co-stimulatory molecules (signal 2), the binding of self antigens presented in MHC molecules to the TCR on naive T cells, results in anergy. Moreover, if naive T cells do become activated they express an addi- tional receptor called CTLA-4 which has a greater binding affinity for the B7 molecules than CD28. Binding of CTLA-4 to B7 results in a negative signal to the T cells resulting in inhibition of T cell activity (Topic F4).
G2 – Central and peripheral tolerance 147
Th APC
CD28
(1)
Tc Tissue
cell (1)
Th APC
(1)
Tc Tissue
cell (1)
(2)
CD28 (2)
CD28 B7 (CD80, CD86) Anergy (signal 1 alone) Immune reactivity
(signal 1 ⴙ signal 2)
Fig. 2. T cell anergy. Th and Tc (including those that are self reactive) cannot be activated by one signal. Binding of B7 (CD80, CD86) on the APC/tissue cell to CD28 provides a second signal to the T cells leading to their activation.
B cell anergy
Self-reactive B cells require T cell help in order to respond to T-dependent anti- gens. Since most self-reactive T cells have been deleted during thymic matura- tion, self-reactive B cells on contact with self antigens do not receive the required co-stimulatory signals (signal 2) from T helper cells and consequently become anergic (Fig. 3). Engagement of the B cell co-stimulatory molecules CD40 and B7 by CD154 and CD28 on T cells, as well as certain cytokines (IL-2, IL-4, IL-5, IL-6), are required for activation (Topic E2).
Activation-induced cell death
Fas/FasL (CD95/CD95L) interaction is directly responsible for AICD. This is important in maintaining immunological as well as physiological homeostasis by eliminating unnecessary cells through apoptosis. Activated T lymphocytes can express both the receptor protein Fas and its ligand (FasL), whereas B cells mainly express Fas. Peripheral tolerance may be facilitated by interaction between activated T cells and B cells (and, perhaps under certain conditions, other T cells) resulting in apoptosis (Fig. 4). In addition, T cells activated to kill
self cells may themselves be killed by interaction with FasL expressed by certain somatic cells, e.g. those in the eye and testis (Topic L3) thus preventing killing of these self cells. This may also be a strategy used by tumor cells to prevent their demise by cytotoxic T cells.
148 Section G – Regulation of the immune response
Th2 B
CD28
CD40 Anergy
Th2 B
CD154
(1)
(1)
(2) CD40
B7 Immune
reactivity
Cytokines
Help from T cells (signal 1 signal 2) No help from T cells (no signal 2)
Tc
Tc Fas
FasL (1)
(2)
Self reactive T and B cells
B cell death
Tc cell death
Self-cells expressing FasL e.g. eye, testes
B
Fig. 4. Activation-induced cell death (AICD) in peripheral tolerance. Tc cells may kill self-B cells expressing Fas(1) and because Tc can also express Fas on activation, may themselves be killed by tissue cells expressing FasL:CD178(2).
Fig. 3. B cell anergy. B cells require triggering through their CD40 molecules to progress through activation and maturation. Interaction of CD28 on T cells with B7 on B cells is necessary to induce expression of CD154 (CD40 ligand). This binds to CD40 on the B cell, acting as the second signal for activation.
Section G – Regulation of the immune response