Regulation of T cell activation by CD28 and CTLA4.

In this article we have reviewed recent studies concerning the roles of CD28 and CTLA4 in controlling T cell activation. CD28 appears to have a dual role promoting both T cell proliferation and survival of activated T cells (Figure 2). Signaling through CD28 results in the upregulation of both intrinsic and extrinsic survival factors which are capable of acting independently to directly enhance cell survival. One way in which this enhancement may be accomplished is through the direct suppression of cell death pathways. This mechanism is supported by the data indicating that induction of the survival gene, bcl-xL, can override Fas induced cell death and that the kinetics of Bcl-xL expression correlate well with the susceptibility of normal T cells to apoptosis initiated by Fas-Fas ligand interactions. The down regulation of an immune response is also a critical control point in the maintenance of immune homeostasis. Fas and now CTLA4 have both been identified as crucial negative regulators of lymphocyte activation as demonstrated by the lymphoproliferative defects present in both lpr and CTLA4-deficient mice. Fas exerts its effects through a programmed cell death pathway mediated by the ICE-like family of proteases. The mechanism by which CTLA4 acts to down regulate proliferation is less clear (Figure 2). One possibility suggested by the data from Gribben and colleagues is that signaling through CTLA4 may induce apoptosis in previously activated cells. Whatever mechanism(s) CTLA4 utilizes to modulate proliferation, they are likely to become active 48-72 hours after activation when cell surface expression of CTLA4 peaks, again correlating with the decreased expression of Bcl-xL. It will be interesting to determine if CTLA4 signaling is specifically required for the down regulation of cell survival factors such as Bcl-xL and IL-2 and whether these effects are influenced directly through crosslinking of CTLA4 or indirectly as downstream effects of an inducible inhibitory pathway. Although the mechanistic details remain to be elucidated, CD28 and CTLA4 appear to play important and complex roles in the control of immune homeostasis.