Control of T cell hyperactivation in IL-2-deficient mice by CD4+CD25- and CD4+CD25+ T cells: evidence for two distinct regulatory mechanisms

Abstract

In IL‐2‐deficient mice, antigen‐activated CD4 T cells accumulate and cause lethal immune pathology. Wild‐type cells of hematopoietic origin present in the same animal are able to prevent this hyperactivation of T cells, but the mechanisms and cells controlling the IL‐2‐deficient cells are unknown. Here we show that IL‐2– CD4 cells with an ovalbumin‐specific transgenic TCR (IL‐2– OVAtg) undergo both clonal expansion and clonal contraction when transferred to euthymic recipients and challenged with antigen, but continuously expand in athymic hosts. Cotransfer of wild‐type CD4 T cells prevents the accumulation of IL‐2‐deficient cells. On the residual IL‐2– TCRtg cells CD69 and CD25 are up‐regulated, suggesting that activation per se is not suppressed and that the cells had received an IL‐2 signal. Since IL‐2 is able to restore the defective antigen‐induced cell death (AICD) of IL‐2‐deficient T cells in vitro, paracrine IL‐2 provided by the wild‐type CD4 cells may thus be able to allow clonal contraction of IL‐2‐deficient cells also in vivo. Interestingly however, regulatory CD4+CD25+ cells also efficiently contain the clone size of antigen‐stimulated IL‐2‐deficient T cells. Since CD4+CD25+ cells do not produce IL‐2, this suggests a mechanism of suppression distinct from paracrine IL‐2 delivery. In keeping with this, the residual IL‐2– TCRtg cells recovered after cotransfer of regulatory CD4+CD25+ cells do not show increased CD25 or CD69 expression, suggesting that they had not received paracrine IL‐2 and that clonal containment occurred at the level of initial activation rather than clonal contraction by AICD. IL‐2 deficiency therefore mayupset T cell homeostasis by two distinct mechanisms: the failure to program expanding T cells for apoptosis, and the failure to generate functional CD4+CD25+ regulatory cells.

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

“…The abnormal lymphoproliferation observed in IL-2-KO mice strictly correlates with their inability to generate T reg [27]. Differently from T reg, CD4 + CD25 -lymphocytes require IL-2 for amplification of Ag specific response but not for their homeostatic maintenance [20,28].…”

Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL‐)two to tango

“…Paradoxically, strong T cell hyperproliferation and autoimmune diseases are observed in mice deficient for IL-2 or components of its receptor [20][21][22][23]. This unexpected pathology can be explained by a reduced number of Treg or their functional impairment [24][25][26][27][28][29], since transfer of wildtype Treg into neonatal IL-2R-deficient mice prevents disease development [24,26,28,30]. IL-2 mainly plays a role for the peripheral expansion and maintenance of Treg [1,18,31] rather than their thymic generation since Treg develop in IL-2-deficient mice [16,28].…”

Enhanced signaling through the IL-2 receptor in CD8+T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8+T cells rather than promotion of cell death

“…Thus, the increased proliferation observed after antigen stimulation of IL-2-deficient CD4 ϩ T cells may be caused in part by the increased proliferative response of effector and memory T cells after antigen stimulation (37). The absence of IL-2 in IL-2 Ϫ/Ϫ mice also interferes with the development and function of CD4 ϩ CD25 ϩ T regulatory cells (12,13), which could contribute to a hyperproliferative T cell response to antigen (13). Finally, the contrasting results could potentially reflect inherent differences in the responses of CD4 ϩ and CD8 ϩ T cells to IL-2R signaling after antigen stimulation.…”

“…IL-2 Ϫ/Ϫ mice exhibit only mild immunodeficiency (9), but T cells from IL-2 or CD25-knockout mice exhibit decreased cell death after activation (8), and the mice demonstrate marked accumulation of lymphocytes, generally succumbing to fatal T cellmediated autoimmune diseases (10,11). However, concluding the physiologic role of IL-2 in peripheral T cell responses from these mice may be misleading, because such mice may also have confounding defects in thymic selection and͞or production of regulatory CD4 ϩ and CD8 ϩ T cells (12,13).…”