CD28 CO‐STIMULATION AMPLIFIES TCR SIGNALS AND BLOCKS APOPTOSIS
As we have frequently noted, naive T‐cells typically require two signals for proper activation: one derived from TCR ligation (signal 1) and the other provided by simultaneous engagement of CD28 on the T‐cell (signal 2) by CD80 (B7.1) or CD86 (B7.2) on the DC (Figure 7.3). Indeed, T‐cells derived from CD28‐deficient mice, or cells treated with anti‐CD28 blocking antibodies, display severely reduced capacity to proliferate in response to TCR stimulation in vitro and in vivo. Moreover, CD28 deficiency also impairs T‐cell differentiation and the production of cytokines required for B‐cell help. Similar effects are also seen when CD80 or CD86 expression is interfered with. So what does tickling the CD28 receptor do that is so special?
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| Figure 7.3 Activation of resting T‐cells. Interaction of co‐stimulatory molecules leads to activation of resting T‐lymphocyte by antigen‐presenting cell (APC) on engagement of the T‐cell receptor (TCR) with its antigen–MHC complex. Engagement of the TCR signal 1 without accompanying co‐stimulatory signal 2 leads to anergy. Note, a cytotoxic rather than a helper T‐cell would, of course, involve coupling of CD8 to MHC class I. Signal 2 is delivered to a resting T‐cell primarily through engagement of CD28 on the T‐cell by B7.1 or B7.2 on the APC. ICAM‐1, intercellular adhesion molecule‐1; LFA‐1, lymphocyte function‐associated molecule‐1; VCAM‐1, vascular cell adhesion molecule‐1; VLA‐4, very late antigen‐4 |
Well, the simple answer is that we do not really know what kind of signal CD28 co‐stimulation produces that is radically different from the signals produced upon stimulation of the TCR complex, as several of the same signaling pathways are triggered. CD28 is expressed on the plasma membrane of naive as well as activated T‐cells as a 44 kDa homo‐dimer, the cytoplasmic domain of which lacks any intrinsic enzyme activity. The cytoplasmic tail of CD28 does, however, contain tyrosinebased motifs that, upon phosphorylation at these residues, recruit phosphatidylinositol 3‐kinase (PI3K) and Grb2. Thus, upon CD28 cross‐linking, signals are propagated via PI3K that can impact upon multiple signaling pathways, including cell survival, cell metabolism, and protein synthesis. CD28‐mediated activation of PI3K is important for the suppression of apoptosis, which appears to be achieved via the downstream target of this pathway, the PkB/Akt kinase. The latter kinase regulates transcription factors that result in increased expression of the anti‐apoptotic Bcl‐xL protein. By upregulating Bcl‐xL, CD28 stimulation blocks TCR‐mediated signals that would otherwise result in apoptosis (a process called activation‐induced cell death (AICD)) (see Videoclip 2). PI3K has also been implicated in phosphorylating Itk, which in turn can phosphorylate PLCγ, which, as we discussed earlier, has an important role in IP3 generation downstream of TCR stimulation. Thus, PI3K activation via CD20 co‐stimulation may synergize with the TCR to promote PLCγ activation.
Grb2 docks onto the same
motif within the cytoplasmic tail of CD28 as PI3K and can activate the Ras
pathway via its associated guanine‐nucleotide exchange factor SOS, as discussed earlier.
Although early studies
suggested that CD28 stimulation might result in qualitatively different
signals to those that are generated through the TCR, many studies suggest that
this might not be the case. Instead, these studies suggest that while CD28
engagement might activate pathways within the T‐cell that TCR stimulation alone does not, the
primary purpose of co‐stimulation through CD28 may
be to quantitatively amplify or stabilize signals through the TCR by
converging on similar transcription factors such as NFκB and NFAT, which are
critical for IL‐2 production. In support of
this view, microarray analyses of genes upregulated in response to TCR ligation
alone, versus TCR ligation in the presence of CD28 co‐stimulation, found, rather
surprisingly, that essentially the same cohorts of genes were expressed in both
cases. Although signals through CD28 enhanced the expression of many of the
genes switched on in response to TCR ligation, no new genes were expressed.
This indicates that CD28 co‐stimulation may be required
in order to cross signaling thresholds that are not achievable via TCR ligation
alone. One is reminded here of the choke that earlier generations of cars were
supplied with to provide a slightly more fuel‐rich mixture to help start a cold engine. CD28 co‐stimulation of naive T‐cells may serve a similar
purpose, with the CD28 “choke” no longer needed when these cells have warmed up
as a result of previous stimulation.
The requirement for two
signals for T‐cell activation is a very
good way of minimizing the likelihood that T‐cells will respond to self antigens. Because T‐cell receptors are generated
randomly and can, in principle, recognize almost any short peptide, the immune
system needs a way of letting a T‐cell know that particular (i.e., nonself) peptides should be responded to whereas others (i.e., derived
from self ) should not. The fact that CD80/CD86 molecules are only upregulated
on APCs that have been stimulated with a PAMP provides quite a clever way of
ensuring that only APCs that have encountered microorganisms are able to
properly present peptides to T‐cells. Once again, we see
the guiding hand of the innate immune system helping to qualify what represents
“danger” and what does not. So, let
us now turn to the issue of what happens downstream of a successful T‐cell activation event.
