IL2 in the negative control of lymphocyte proliferation

Autoimmunity in IL-2-deficient animals

The precise role of IL-2 in vivo is not well understood. An important tool for studying this question

is provided by gene knockout mice produced after homologous recombination. In IL-2_/ " animals the ontogeny of the immune system is not dramatically affected, as demonstrated by the normal development of lymphoid organs and the presence of the major lymphocyte subsets. However IL-2_/ animals have an overproduction of lymphocytes, which is morphologically reflected by lymphoid organ hyperplasia. This observation is surprising since IL-2 was first described as a T cell growth factor.

As expected, the immune response of IL-2_/~ mice is abnormal at the T and B cell level. The in vivo cytotoxic response against viruses is reduced, although in vitro cytotoxic responses can be restored by addition of IL-2.

The most striking observation made with IL-2 animals is the development of an autoimmune syndrome. The intensity of the disease is dependent both on environmental factors and the genetic background of the animals. Fifty per cent of IL-2_/" mice in a 129/Ola X C57B16 genetic background die of autoimmune hemolytic anemia before 9 weeks of age. All animals that survive past 10 weeks of age develop an inflammatory bowel disease comparable to ulcerative colitis in humans. Mice kept in germ-free conditions do not develop the disease. The data obtained with IL-2_/" mice as well as with IL-2Ra_/" and IL-2R3"/_ animals indicate that there may be a defect in cell apoptosis in these animals.

IL-2 in the control of apoptosis

Shortly after antigen recognition an autocrine loop is established based on the coexpression of IL-2 and the IL-2R by T cells, which functions to drive responding cells through the cell cycle. IL-2 also promotes the survival of T cells in culture, presumably by inducing the expression of Bcl-2, a protein that protects cells from passive apoptotic cell death. In vivo this mechanism may be related to the persistence of some memory cells.

On the other hand, several recent studies have demonstrated that clonal expansion of activated T cells can be controlled by the induction of programmed cell death of some activated lymphocytes. The major pathway of this activation-induced cell death (AICD) involves the interaction of Fas expressed by activated T and B cells and Fas ligand produced by a subset of activated T cells. IL-2 is a critical determinant of AICD: addition of IL-2 to stimulated T cell clones increases AICD whereas anti-IL-2 antibodies reverse the deletion of these cells. The effect of IL-2 on AICD may be explained by the acquisition of susceptibility to Fas-mediated apoptosis after treatment with IL-2, but not by increased Fas expression.

IL-2-dependent immune responses are transient since IL-2-induced activation and clonal expansion is followed by AICD. Furthermore IL-2 appears to be critical for triggering a mechanism that regulates self-tolerance and prevents pathological autoimmunity.

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