CO-STIMULATORY MOLECULES ARE ESSENTIAL FOR T CELL ACTIVATION
Crucially, co-stimulatory molecules act together with
the antigen-specific signals before the T cell is sanctioned for proliferation. Co-stimulatory and antigen-specific signals must be present simultaneously on the same cell. Overall, antigen presentation through MHC class I or class II molecules can be split into four stages adhesion, antigen-specific activation, co-stimulation, and cytokine signaling (see Fig. 7.1).
ICAM-1 (CD54), interact with the integrin, lymphocyte functional antigen-1 (LFA-1 or CD11a/CD18), present on all immune cells. If mouse cells are transfected with both human MHC and human ICAM-1, their capacity to act as human APCs is augmented. When the T cell encounters the appropriate MHC moleculepeptide, which happens rarely except during an ongoing infection, a conformational change in LFA-1 on the T cell, signaled via the TCR, results in tighter binding to ICAM-1, which results in prolonged cellcell contact. The joined cells can exist as a pair for long periods, allowing time for the T cell to proliferate and differentiate. The specific MHC moleculepeptideTCR interaction, though necessary, is not sufficient to fully activate the T cell. A second signal is required, otherwise the T cell will become unresponsive. This second signal, also referred to as co-stimulation, is of crucial importance. Some co-stimulatory molecules that interact with ligands on the T cells surface are shown in Fig. 7.16. The most potent co-stimulatory molecules known are B7s, which are members of the immunoglobulin superfamily molecules; they include B7-1 (CD80) and B7-2 (CD86).
Critical molecules involved in antigen presentation
T cell CD2
LFA-1
TCR
IL-1 IL-6 TNF! IL-12 IL-15
p56Lck
CD4
LFA-3 (CD48)
ICAM-1
class II APC
Several other B7-related molecules are beginning to
emerge. B7s exist as homodimers on the cell surface. These proteins are constitutively expressed on DCs, but can be upregulated on monocytes, B cells, and probably other APCs. Upregulation of co-receptors is stimulated by inflammation and by interaction of microbial products with Tolllike receptors (TLRs, see Fig. 6.24) on the APC. Co-receptors are the ligands for other immunoglobulin superfamily molecules CD28 and its homolog CTLA-4 (CD152), which is expressed after T cell activation. CD28 is the main co-stimulatory ligand expressed on naive T cells. CD28 stimulation: has been shown to prolong and augment the production of IL-2 and other cytokines; and is probably important in preventing the induction of tolerance. Although the CD28B7 interaction is extremely important, CD28 knockout mice do respond to antigen, but require higher doses, so CD28 triggering is not obligatory, even for naive T cells. In CD28 knockout mice other co-stimulatory signals probably replace that delivered by CD28B7. CTLA-4, the alternative ligand for B7, is an inhibitory receptor limiting T cell activation, resulting in less IL-2 production. Thus CD28, constitutively expressed, initially interacts with B7, leading to T cell activation. Once this has peaked, the upregulation of CTLA-4 with its higher affinity limits the degree of activation because available B7 will interact with CTLA-4 (Fig. 7.17). Q. What effect would you expect to see in mice that have the CTLA-4 gene knocked out? A. They suffer from an aggressive lymphoproliferative disorder, because they do not inactivate dividing T cells efficiently (see Fig. 7.17).
Role of CTLA-4 in controlling T cell activation
CD28
activation division IFN" GM-CSF IL-4 TNF#
B7-1/B7-2 (CD80/CD86)
Fig. 7.16 The molecules involved in the interaction between T
cells and APCs. The various cytokines and their direction of action are also shown. In humans LFA-3 (CD58) acts as a ligand for CD2, but in rodents CD48 performs this function.
inactivation T
CTLA-4
CD28 B7
B7
APC
APC
Fig. 7.17 Before activation, T cells express CD28, which
ligates B7-1 and B7-2 on APCs (e.g. B cells). After activation, CTLA-4 is expressed, which is an alternative high-affinity ligand for B7. CTLA-4 ligates B7, so the T cells no longer receive an activation signal.