T Cells as Sources and Targets of TNF: Implications for Immunity and Autoimmunity

Abstract

TNF is a pleiotropic cytokine produced by many cell types upon different stimuli and in various physiological and pathological conditions. In this review, we focus on the role of TNF in T cell responses as demonstrated by in vitro and in vivo observations in mice and humans. TNF has an impact on all aspects of T cell biology such as development in the thymus, peripheral homeostasis, primary antigenic responses, apoptosis, effector functions, memory cell formation and tolerance induction and maintenance. In most cases, TNF has an immunostimulatory role in T cell responses; however, under certain conditions, TNF can exert immunomodulatory effects on T cells. We also review how T cell-derived TNF is an important component of T cell immunity as exemplified by many studies involving intracellular pathogens and tumors. Finally, we summarize how TNF T cells interplay contributes to pathology in autoimmune disorders and what is known about the effect of widely used TNF blockers on T cell differentiation/function.

An immunomodulatory peptide related to frenatin 2 from skin secretions of the Tyrrhenian painted frog Discoglossus sardus (Alytidae)

“…As D. sardus skin secretions do not contain the cationic ␣-helical hostdefense peptides that are produced in the skins of several other frog species [10,11], the system of adaptive immunity may be of particular importance in this animal. Pro-inflammatory cytokines function as immunostimulatory agents and several compounds that stimulate cytokine release are in clinical practice [7,25]. We suggest, therefore, that a possible role for frenatin 2D is activation of macrophages in frog skin to produce cytokines that stimulate the adaptive immune response to invading microorganisms.…”

Tumor Necrosis Factor Alpha Production from CD8+T Cells Mediates Oviduct Pathological Sequelae following Primary Genital Chlamydia muridarum Infection

“…Additionally, in TNF-␣-deficient mice, transferred TNF-␣ ϩ/ϩ CD8 ϩ T cells were able to induce oviduct pathology that was intermediate between those of wildtype C57BL/6 mice and TNF-␣ Ϫ/Ϫ mice, suggesting that TNF-␣ production from both CD8 ϩ T cells and non-CD8 ϩ T cells may mediate chlamydial pathogenesis. TNF-␣ can be produced by a broad variety of cell types, including fibroblasts, macrophages, mast cells, and lymphocytes (4). TNF-␣ binds to two receptors, TNF-R1 and TNF-R2, and is known to activate at least three different signaling cascades (5,43): (i) NF-B signaling leading to very strong anti-apoptotic effects, (ii) JNK pathway leading to generally proapoptotic effects, and (iii) FIG.…”

Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination

“…However, recent findings have demonstrated that the liver-damaging effects of TNF␣ in this disease model are largely mediated indirectly via the activation iNKT cells. [33][34][35] In addition, TNF␣ mediates an increased influx of circulating lymphocytes into the hepatic sinus and their subsequent local proliferation via blastoid formation, which further contributes to liver destruction. [33][34] The high expression levels of Toso in NKT cells and in activated cytotoxic T cells, together with a lack of Toso expression in hepatocytes therefore suggests the following scenario.…”

“…[33][34][35] In addition, TNF␣ mediates an increased influx of circulating lymphocytes into the hepatic sinus and their subsequent local proliferation via blastoid formation, which further contributes to liver destruction. [33][34] The high expression levels of Toso in NKT cells and in activated cytotoxic T cells, together with a lack of Toso expression in hepatocytes therefore suggests the following scenario. On TNF␣-engagement Toso Ϫ/Ϫ leukocytes are more likely to undergo apoptosis and only few potentially autodestructive immune cells get activated in Toso Ϫ/Ϫ mice.…”