ABSTRACT
T he recent characterization o f several costimulatory interactions between antigen presenting cells and T cells represents a major advance in our understanding o f both normal adaptive immune responses and pathologic autoimmune responses. Furthermore, characterization o f these costimulation pathways has suggested a number o f new approaches for directing more specific immunosuppressive therapy for chronic au toimmune diseases such as systemic lupus erythematosus (SLE). Many experiments have now established the validity the two-signal hypothesis o f Bretscher and Cohn.1 These studies have established that the first signal, provided by antigen specific stimulation o f the T cell antigen receptor, is a necessary, but insufficient stimulus for maximal T cell activation and subsequent effector function. T cell activation, as manifested by IL-2 pro duction and T cell proliferation, further requires a second, or costimulatory signal.2,3 A variety o f specific interactions between T cells and antigen presenting cells (APC), or other accessory cells, can provide this second signal. However, the interaction between CD 28 expressed on T cells and B7 molecules expressed on antigen presenting cells and activated B cells appears to provide the major costimulatory signal to T cells in a wide variety o f adaptive immune responses.4 CD 28 is constitutively expressed on the majority o f T cells,5 while its ligands are expressed on the surface o f activated, but not resting APC.6 Three B7 ligands have been described on activated human B lymphocytes; B7-1 (CD 80), B7-2 (CD86) and B7-3, and two ligands, m B7-l and mB7-2 have been identified o f mouse B cells. Studies o f CD28-deficient mice suggest that CD 28 is the predominant receptor responsible for B7-dependent T cell activation.7 More recently, an inducible costimulatory molecule called ICO S that is structurally related to CD 28, along with its ligand B7h, that is also homologous to other B7 molecules, have been described.8"10 These costimulatory molecules may deliver both complementary and unique costimulatory signals to T cells.11,12
CTLA4 is a T cell surface receptor that also binds B7 molecules and that has 20% sequence homology and significant structural homology to C D 28 .13 However, CTLA4 binds both C D 80 and C D 86 with much higher avidity than does C D 28 and in contrast to CD 28, CTLA4 is only expressed on activated T cells. Although originally classified as a costimulatory molecule, it has become clear that a major function o f CTLA 4 is to negatively regulate T cell function.14,15 The kinetics o f CTLA4 induction and the high avidity of binding to B7 molecules imply that one role o f CTLA4 is to limit T cell activation
CTLA-4 in Autoimmune Disease, edited by Flemming Pociot. © 2004 Eurekah.com.
