Regulatory T cells restrain CD4+ T cells from causing unregulated immune activation and hypersensitivity to lipopolysaccharide challenge.

Regulatory T cells (Tregs) are essential for maintenance of peripheral tolerance, and defects in Treg function have been linked to several autoimmune diseases. We previously reported that depletion of Tregs resulted in mortality to an otherwise nonlethal dose of LPS or Escherichia coli challenge. In this study, we investigated the mechanism by which Treg depletion leads to enhanced susceptibility to LPS. Using different murine lymphocyte gene knockout models, we show that the enhanced sensitivity to LPS following Treg depletion is mediated by T cells. SCID or RAG1-deficient mice, which lack T and B cells, do not show enhanced susceptibility to LPS. However, reconstitution of SCID mice with wild-type CD4(+) T cells restored Treg depletion-induced sensitivity to LPS. This CD4(+) T cell-mediated hypersensitivity to LPS challenge in the absence of Tregs was also observed upon reconstitution of SCID mice with CD4(+) T cells from CD25 knockout mice (which lack functional Tregs). Additionally, depletion of Tregs leads to increased CD4(+) T cell proliferation and proinflammatory cytokine production in response to LPS challenge. Some CD4(+) T cells express TLR4, and pretreatment of CD4(+) T cells with LPS dramatically enhanced their ability to induce inflammatory cytokine production by macrophages. Collectively, our results indicate that in the absence of functional Tregs, CD4(+) T cells are pathologic and contribute to exaggerated immune activation that is detrimental for survival in LPS-induced acute inflammation. Our data also provide evidence for direct activation of CD4(+) T cells by LPS through TLR4.