Immunopathology of interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene.

Abstract

SummaryIntedeukin (IL) 2-deficient mice develop a fatal immunopathology characterized by lymphadenopathy, splenomegaly, T cell infiltration of the bone marrow, loss of B cells, anemia, and inflammation of the gut. The thymus dependence of these disease symptoms was tested by introducing the IL-2 mutation into athymic mice. With the exception of an increase in CD8+ intrahepatic oLlp T cells, IL-2 deficiency had no detectable effect on leukocyte composition or health of athymic mice, indicating a key role for thymus-derived T cells in the initiation of disease and demonstrating that B cell development and survival are independent of IL-2. In adoptive transfer studies, lymph node and spleen cells from euthymic IL-2-deficient mice induced disease in athymic mice with an intact IL-2 gene, suggesting that thymus-independent IL-2-expressing cells are unable to control the development of immune pathology . Both IL-2+ and IL-2 -' -bone marrow cells repopulated the thymus and the peripheral T cell compartment of the recombination activator gene 2-deficient recipients, and chimeras that had received IL-2-deficient bone marrow developed immune pathology . Disease development was, however, fully or at least partially prevented when 30% ofthe bone marrow inoculum was derived from mice able to express IL-2. These results demonstrate that the IL-2 deficiency syndrome depends on the intrathymic differentiation ofT cells carrying the IL-2 mutation, and that the abnormal activation of IL-2-deficient lymphocytes can be controlled by thymus-derived but not thymusindependent lymphocytes .

IL-2, Regulatory T Cells, and Tolerance

“…The first suggestion came from studies in which RAG-2 Ϫ/Ϫ mice were reconstituted with bone marrow containing a 30%:70% mixture of IL-2-replete and IL-2-deficient cells. Autoimmune pathology failed to develop in these mice, indicating that IL-2-replete T cells can prevent IL-2-deficient T cells from undergoing uncontrolled expansion and initiating autoimmune disease (30), which is consistent with a Treg mechanism. It was later shown that mice deficient for the IL-2 or IL-2R␤ genes lack CD4 ϩ CD25 ϩ T cells (36,58,59).…”

“…Finally, IL-2 Ϫ/Ϫ nude mice, which lack a functional thymus, do not develop any autoimmune manifestations, indicating that thymic rather than extrathymic T cells are required for the pathological process. Indeed, transfer of lymphocytes from euthymic IL-2 Ϫ/Ϫ mice into athymic IL-2 ϩ/ϩ mice results in autoimmunity; therefore, IL-2-replete extrathymic T cells are unable to control the dysregulated activity of IL-2-deficient thymically derived lymphocytes (30).…”

Differential role of IL‐2R signaling for CD8+ T cell responses in acute and chronic viral infections

“…Furthermore, the generation of mice deficient in IL-2 or its receptor has highlighted the importance of IL-2 in regulatory T cell (Treg) development. Both IL-2-and IL-2R-deficient mice are prone to develop autoimmunity and may develop lymphoproliferative diseases [12][13][14][15][16][17]. Thus, IL-2 is implicated in promoting as well as inhibiting T cell responses [18].…”

The IL-2/CD25 Pathway Determines Susceptibility to T1D in Humans and NOD Mice

“…Moreover, might variation in these pathways alter susceptibility to autoimmune diseases in addition to T1D? IL-2 −/− knockout mice develop autoimmunity, including a type of inflammatory bowel disease [27][28][29], while mice deficient in CD25 show an initial normal lymphoid development, but subsequently develop peripheral lymphoid organ enlargement as polyclonal T and B cells undergo expansion and activation-induced cell death ) [14] (AICD) is impaired, and with age autoimmunity develops [30]. These observations are consistent with the development of T1D in NOD mice associated with reduced IL-2 levels [18,19], and furthermore, Idd3 alleles are known to affect the development of a number of other autoimmune diseases, including autoimmune ovarian dysgenesis [31], experimental autoimmune encephalomyelitis [32], and Sjögren's syndrome-associated manifestations [33,34].…”