Article Update

Thursday, November 5, 2020



As we have frequently noted, naive Tcells 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 Tcell (signal 2) by CD80 (B7.1) or CD86 (B7.2) on the DC (Figure 7.3). Indeed, Tcells derived from CD28deficient mice, or cells treated with antiCD28 blocking antibodies, display severely reduced capacity to proliferate in response to TCR stimulation in vitro and in vivo. Moreover, CD28 deficiency also impairs Tcell differentiation and the production of cytokines required for Bcell 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?

Activation of resting T‐cells
Figure 7.3 Activation of resting Tcells. Interaction of costimulatory molecules leads to activation of resting Tlymphocyte by antigenpresenting cell (APC) on engagement of the Tcell receptor (TCR) with its antigen–MHC complex. Engagement of the TCR signal 1 without accompanying costimulatory signal 2 leads to anergy. Note, a cytotoxic rather than a helper Tcell would, of course, involve coupling of CD8 to MHC class I. Signal 2 is delivered to a resting Tcell primarily through engagement of CD28 on the Tcell by B7.1 or B7.2 on the APC. ICAM1, intercellular adhesion molecule1; LFA1, lymphocyte functionassociated molecule1; VCAM1, vascular cell adhesion molecule1; VLA4, very late antigen4

Well, the simple answer is that we do not really know what kind of signal CD28 costimulation 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 Tcells as a 44 kDa homodimer, 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 3kinase (PI3K) and Grb2. Thus, upon CD28 crosslinking, signals are propagated via PI3K that can impact upon multiple signaling pathways, including cell survival, cell metabolism, and protein synthesis. CD28mediated 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 antiapoptotic BclxL protein. By upregulating BclxL, CD28 stimulation blocks TCRmediated signals that would otherwise result in apoptosis (a process called activationinduced 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 costimulation 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 guaninenucleotide 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 Tcell that TCR stimulation alone does not, the primary purpose of costimulation 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 IL2 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 costimulation, 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 costimulation 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 fuelrich mixture to help start a cold engine. CD28 costimulation of naive Tcells 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 Tcell activation is a very good way of minimizing the likelihood that Tcells will respond to self antigens. Because Tcell receptors are generated randomly and can, in principle, recognize almost any short peptide, the immune system needs a way of letting a Tcell 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 Tcells. 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 Tcell activation event.

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