Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, and the resultant severe hypotension play a central role in the pathophysiological process. Mitogen-activated protein (MAP) kinase cascades are crucial in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAP kinase. Thus, we hypothesize that knockout of the Mkp-1 gene results in prolonged MAP kinase activation, augmented cytokine production, and increased susceptibility to endotoxic shock. Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge. We demonstrate that upon LPS challenge, Mkp-1−/− cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-α and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-α, IL-6, and IL-10 than do wild-type mice. Consequently, Mkp-1 knockout mice develop severe hypotension and multiple organ failure, and exhibit a remarkable increase in mortality. Our studies demonstrate that MKP-1 is a pivotal feedback control regulator of the innate immune responses and plays a critical role in suppressing endotoxin shock.

CIITA activates the expression of multiple genes involved in antigen presentation and it is believed to be required for both constitutive and IFN gamma-inducible expression of these genes. To understand the role of CIITA in vivo, we have used gene targeting to generate mice that lack CIITA. CIITA-deficient (-/-) mice do not express conventional MHC class II molecules on the surface of splenic B cells and dendritic cells. In addition, macrophages resident in the peritoneal cavity do not express MHC class II molecules upon IFN gamma stimulation nor do somatic tissues of mice injected with IFN gamma, in contrast with wild-type mice. The levels of Ii and H-2M gene transcripts are substantially decreased but absent in CIITA (-/-) mice. The transcription of nonconventional MHC class II genes is, however not affected by CIITA deficiency. A subset of thymic epithelial cells express MHC class II molecules. Nonetheless, very few mature CD4 T cells are present in the periphery of CIITA (-/-) mice despite MHC class II expression in the thymus. Consequently, CIITA(-/-) mice are impaired in T-dependent antigen responses and MHC class II-mediated allogeneic responses.

Conventional understanding of CD4 T cell development is that the MHC class II molecules on cortical thymic epithelial cell are necessary for positive selection, as demonstrated in mouse models. Clinical data, however, show that hematopoietic stem cells reconstitute CD4 T cells in patients devoid of MHC class II. Additionally, CD4 T cells generated from human stem cells in immunocompromised mice were restricted to human, but not mouse, MHC class II. These studies suggest an alternative pathway for CD4 T cell development that does not normally exist in mice. MHC class II is expressed on developing human thymocytes, indicating a possible role of MHC II on thymocytes for CD4 T cell generation. Therefore, we created mice in which MHC class II is expressed only on T lineage cells. Remarkably, the CD4 compartment in such mice is efficiently reconstituted with unique specificity, demonstrating a novel thymocyte-driven pathway of CD4 T cell selection.

T lymphocytes rely on several metabolic processes to produce the high amounts of energy and metabolites needed to drive clonal expansion and the development of effector functions. However, many of these pathways result in the production of reactive oxygen species (ROS), which have canonically been thought of as cytotoxic agents due to their ability to damage DNA and other subcellular structures. Interestingly, ROS has recently emerged as a critical second messenger for T cell receptor signaling and T cell activation, but the sensitivity of different T cell subsets to ROS varies. Therefore, the tight regulation of ROS production by cellular antioxidant pathways is critical to maintaining proper signal transduction without compromising the integrity of the cell. This review intends to detail the common metabolic sources of intracellular ROS and the mechanisms by which ROS contributes to the development of T cell-mediated immunity. The regulation of ROS levels by the glutathione pathway and the Nrf2-Keap1-Cul3 trimeric complex will be discussed. Finally, T cell-mediated autoimmune diseases exacerbated by defects in ROS regulation will be further examined in order to identify potential therapeutic interventions for these disorders.

Class II transactivator (CIITA) is known as a coactivator for MHC class II gene expression in antigen-presenting cells. Surprisingly, when CIITA-/- CD4 T cells were stimulated in the presence of IL-12, they produced not only IFNgamma but also high levels of IL-4. The IL-4 production is due to the accumulation of IL-4 gene transcripts in Th1 cells. This transcriptional control is observed in T cells differentiating to the Th1 but not Th2 lineage, consistent with induction of expression of the CIITA gene in T cells by IFNgamma. Thus, in addition to its role in transactivation of genes involved in antigen presentation, CIITA plays a critical role during the T cell differentiation by negatively regulating the IL-4 gene transcription.