Quantitative and qualitative differences in IL-2 and IL-4 expression in primary and secondary T cell stimulation.

Lymphocytes were concanavalin A (Con A) primed and the signal was withdrawn 4-48 h post-stimulation by alpha-methyl-D-mannopyranoside (alpha MM) treatment. Upon restimulation IL-2 and IL-4 RNA expression was found to be greatly enhanced. Re-expression of lymphokine RNA was dependent on signals delivered by Con A, anti-CD3 antibodies or phorbolester plus ionomycin, and could not be achieved by either IL-2, phorbolester or ionomycin alone. Increased IL-2 re-expression was only possible when alpha MM was added early after primary stimulation, while the ability for enhanced IL-4 RNA re-expression persisted. IL-2 and IL-4 RNA re-expression was characterized by increases in steady state precursor RNA levels and thus, presumably, increased rates of transcription. However, the high accumulation of IL-2 RNA observed upon restimulation was also due to greatly increased RNA stability (greater than 4 h versus 30 min after primary stimulation). Thus, secondary expression of IL-4 RNA is persistent and mostly due to quantitative changes in transcription, whereas enhanced re-expression of IL-2 RNA also results from altered post-transcriptional regulation. This phenotype, however, is only short lived.

Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene.

Mice deficient for interleukin-2 develop normally during the first 3-4 weeks of age. However, later on they become severely compromised, and about 50% of the animals die between 4 and 9 weeks after birth. Of the remaining mice, 100% develop an inflammatory bowel disease with striking clinical and histological similarity to ulcerative colitis in humans. The alterations of the immune system are characterized by a high number of activated T and B cells, elevated immunoglobulin secretion, anti-colon antibodies, and aberrant expression of class II major histocompatibility complex molecules. The data provide evidence for a primary role of the immune system in the etiology of ulcerative colitis and strongly suggest that the disease results from an abnormal immune response to a normal antigenic stimulus.

Development and proliferation of lymphocytes in mice deficient for both interleukins-2 and -4.

Interleukin (IL)-2 and IL-4 are considered as important regulators of growth and differentiation of lymphocytes. We report that in mice made deficient for both IL-2 and IL-4 by gene targeting all major T cell subsets and B cells were normal, indicating that IL-2 and IL-4 are not essential for development of the immune system. Paradoxically, proliferation of T cells was increased in both IL-2 and IL-4-deficient homozygous mice.

[Generalized autoimmune diseases in BALB/c mice with a genetically dependent interleukin-2 deficiency]. / Generalisierte Autoimmunkrankheit in BALB/c-Mäusen mit genetisch bedingtem Interleukin-2-Mangel.

Il-2 has been described as a key cytokine regulating the growth, differentiation and function of lymphocytes. To better understand its in vivo function Il-2 deficient mouse mutants were generated on a mixed (129/Ola x C57BL6) genetic background which predominantly develop an ulcerative colitis-like disease (10). To further elucidate the complex disease syndrome of Il-2-/-mice and to study the possible contribution of genetic factors in its pathogenesis we have bred the IL-2-/-mice to various genetic backgrounds. The resulting phenotypes were analyzed clinically and morphologically and the status of their immune system was assessed. Il-2-/-mice backcrossed to BALB/c genetic background develop a generalized autoimmune disease, which becomes manifest as hemolytic anemia, follicular hyperplasia of lymphoid organs, inflammatory changes of pancreas, liver, heart, lungs and thoracal blood vessels but not of the colon (11). The mutants all die within 5 weeks of age. The changes of the immune system are dominated by an uncontrolled polyclonal activation and proliferation of T and B cells, associated with an increased production of autoantibodies. Treatment of Il-2-/-Balb/c mice with anti-gp39 (CD40L) antibody inhibited activation of B cells and CD8+ T cells, however, it did not affect the activation of CD4+ T cells. In such treated mice amelioration of hemolytic anemia but not of inflammatory lesions in most of the affected organs could be recognized. The primary immunologic change of Il-2-/-mice is obviously an uncontrolled proliferation of CD4+ T cells. It suggests that the in vivo function of IL-2 which is not compensated by other cytokines is the maintenance of self tolerance.

Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells.

Interleukin-2-deficient mice (IL-2-/-) crossed to a BALB/c genetic background develop a lymphoproliferative syndrome with severe hemolytic anemia and die within 5 weeks of age. The presence of autoantibodies of various specificities and inflammatory lesions in several organs are indicative of a generalized auto-immune disease. No alterations of the immune system were observed in 6-day-old animals, but 10-day-old mice already showed an increased proliferation and polyclonal activation of lymphocytes. The treatment of IL-2-/- mice with anti-gp39(CD40L) antibody prevented the disease and indicated that the appearance of activated CD4- T cells (CD44high, CD69-) represents the first alteration of the immune system in IL-2-/- mice. Collectively, our results suggest that an essential role of IL-2 in vivo, which is not compensated by other cytokines, is the maintenance of self tolerance.

Interleukin-2 is indispensable for development of immunological self-tolerance.

Interleukin-2-deficient mice (IL-2(-/-)) manifest severe immune system abnormalities characterized by an uncontrolled activation and proliferation of lymphocytes. A systemic autoimmune syndrome results, and hemolytic anemia leads to early death especially in mice derived from a BALB/c genotype. Remarkably, IL-2 treatment prevents both the activation of the immune system and the development of autoimmune disease. Moreover, adoptive transfer of lymphocytes from IL-2-treated IL-2(-/-) animals confers protection to IL-2(-/-) mice, suggesting that IL-2 induces a postnatal differentiation/maturation of regulatory cells necessary for self- and non-self-discrimination.