TNF was originally discovered due to its potent anti-tumor activity in mice but later emerged as one of immune mediators with critical non-redundant functions in health and disease. TNF-deficient mice fail to mount protective responses against intracellular bacteria, such as Listeria or Mycobacteria, partly due to defective bactericidal granuloma formation or its structural maintenance. TNF is also critical for the structure of peripheral lymphoid tissues. On the other hand, pathogenic overproduction of TNF was implicated in several autoimmune diseases, and therapies based on systemic blockade of cytokine signaling are being widely used in clinic. We are using panels of engineered mice with specific inactivation or enhancement of TNF signaling to uncover the fine balance between beneficial and deleterious physiologic functions of TNF. In particular, we have generated mice allowing us to define the source (type of immunocyte) and molecular form (soluble versus membrane-bound) of TNF with non-redundant specific roles in the structural organization of lymphoid tissues, as well as in pathologies, such as EAE or septic shock. Additionally, we have developed novel "humanized" mouse models allowing side-by-side comparison of the effects of clinically used drugs. One of our goals is to design safer modalities of anti-TNF therapy.