Releasing the brakes on antitumor immune response.

Abstract

AS is the case with firearms, the destructive capacity of the immune system must be carefully aimed and just as carefully regulated. A report by Leach et al. (1 ) in this issue is an encouraging example of how the receptors that regulate immune responsesin this case, CTLA-4, which was discussed in a recent Perspective (2)-can be directly targeted for immunotherapy. T cell activation is normally self-limited so that the immune system returns to a baseline state once the offending antigen has been cleared. Initiation of T cell activation requires two signals, a major histocompatibility complex (MHC) antigen-specific signal delivered through the T cell receptor (3) and a constimulatory signal, the best characterized of which is delivered through the CD28 receptor (4). Each of these receptors has a counterregulatory cousin that recognizes the same ligand but delivers an opposing negative signal. The counterregulatory receptor for the T cell receptor is from the natural killer (NK) receptor gene family [first discovered on NK cells but also expressed on T cells (5)] CTLA-4 is the counterregulatory receptor for CD28; it binds B7 with roughly 10-fold higher affinity than does CD28. Occupancy of CTLA-4 directly counters the effects of CD28 on T cell activation (6): CD28 cross-linking increases lymphokine secretion by activated T cells, whereas CTLA-4 cross-linking decreases lymphokine production. Neither the NK receptor nor CTLA-4 is expressed on resting T cells; rather, they become induced after T cell activation. These delayed kinetics of expression are responsible for the characteristic self-limited nature of T cell activation. The importance of CTLA-4 in T cell homeostasis in vivo is most dramatically exemplified in CTLA-4 knockout mice. These mice develop a severe lymphoproliferative disease with immunologically mediated organ destruction (7). Manipulation of these counterregulatory receptors in vivo has now entered the realm of cancer immunotherapy. Leach et al. have registered a success in this endeavor by injecting antibodies to CTLA-4 (anti-CTLA-4) into mice with tumors,