Maintaining Memory
Although IL-7 is important for memory T cell survival in mice, >20% of human peripheral CD8+ T cells are memory cells with impaired responses to this cytokine. To determine how these IL-7Rαlow memory T cells are maintained in human peripheral blood, Kim et al. (p. 6734 ) assessed the potential involvement of IL-15 in memory cell persistence. The authors first observed that the IL-15R signaling chain was expressed at higher levels in IL-7Rαlow vs IL-7Rαhigh memory cells, as were the transcription factors that induce the IL-15R, T-bet and Eomes. IL-15 treatment induced proliferation of both IL-7Rαlow and IL-7Rαhigh CD8+ memory T cells, while IL-15 treatment combined with TCR triggering restored, in a CD28-independent manner, the TCR-mediated proliferation that is impaired in IL-7RαlowCD8+ memory T cells. Treatment with kinase inhibitors identified involvement of the PI3K/Akt signaling pathway in the IL-15-mediated restoration of memory cell proliferation. The authors suggest that IL-15 may act both to induce a basal level of memory T cell proliferation in the absence of Ag and to interact with the TCR signaling pathway to augment Ag-specific proliferation of IL-7RαlowCD8+ memory T cells.
Shedding LIGHT on Th1 Development
The TNF superfamily member LIGHT has been implicated in T cell costimulation, but its mechanism of action is not well understood. Xu et al. (p. 6901 ) hypothesized that LIGHT regulates Th1 responses via the modulation of IL-12. Experiments utilizing LIGHT-deficient mice or fusion protein-mediated blockade of LIGHT: herpes virus entry mediator (HVEM) interactions demonstrated impairment of IL-12 production and DC maturation, both in vitro and in vivo. Th1 cell differentiation was also inhibited in these experiments, although T cell proliferation was not significantly altered from that of controls. C57BL/6 mice, which are prone to Th1-skewed immune responses, normally resolve Leishmania major infection. However, these mice became dramatically susceptible to disease in the context of LIGHT: blockade, and this susceptibility could be reversed by the exogenous addition of IL-12. In addition, irradiated RAG−/− mice reconstituted with LIGHT−/− or HVEM−/− bone marrow were susceptible to L. major infection, whereas mice reconstituted with wild-type bone marrow were able to heal after infection. These data suggest that LIGHT is required for optimal Th1 development via the regulation of IL-12 production and shed light on both the regulation of Th cell differentiation and the increasingly complex field of T cell costimulation.
TNF in the Liver
Tumor necrosis factor can have both detrimental and beneficial effects in apoptotic liver damage, but the mechanism for such contradictory activities is not known. In a mouse model of experimental hepatitis, TNF induces liver injury in the presence of transcriptional inhibition but protection in its absence, leading Sass et al. (p. 7042 ) to investigate whether TNF could induce genes that mediated its anti-inflammatory effects. They first observed that treating mice with TNF before the induction of liver damage interfered with the expression of the proapoptotic protein Bax and, thus, with the development of mitochondrial apoptosis. The antiapoptotic molecule A20 was identified as the link between TNF and Bax down-regulation, supported by the observation that inhibition of A20 restored the sensitivity of TNF-pretreated mice to hepatic injury and apoptosis. Further analysis clearly identified the pathway responsible for apoptotic inhibition, indicating that TNF-induced overexpression of A20 inhibited NF-κB expression, which then reduced Bax expression and inhibited mitochondrial apoptosis. The elucidation of this antiapoptotic pathway could identify therapeutic targets to down-regulate the inflammatory response in liver disease or injury.
Parental Tolerance
It has been observed in both humans and mice that offspring maintain tolerance to noninherited maternal Ags (NIMA), but the mechanism for this tolerance is unclear. Molitor-Dart et al. (p. 6749 ) hypothesized that NIMA exposure during development and nursing induced T regulatory cells (Treg) that could mediate the observed NIMA effect. The authors found that T cells from NIMA-exposed mice mediated bystander suppression of delayed-type hypersensitivity responses and that the addition of anti-TGF-β or anti-IL-10 Abs reversed the bystander effect. When NIMA-exposed CD4+ T cells were adoptively transferred and then recovered from an “in vivo MLR” system, they showed decreased proliferation and increased surface TGF-β as compared with controls. Donor-specific transfusion was found to increase circulating CD4+CD25+TGF-β+ T cells in NIMA-exposed mice, and the ability of these Treg to induce tolerance of a NIMA-expressing cardiac allograft was assessed. Although all of the control mice rejected the allografts, ∼40% of the NIMA-exposed mice accepted NIMA-expressing allografts whereas 60% rejected these grafts, although with delayed kinetics. Significantly more CD4+CD25+Foxp3+ graft-infiltrating cells were observed in mice that accepted their grafts than in those that rejected them. Importantly, the mice able to accept grafts had greater numbers of Treg infiltrating the graft and producing IL-10 and TGF-β. These data explain the known phenomenon of tolerance to a noninherited maternal haplotype in patients receiving multiple blood transfusions. Exploiting the NIMA effect could lead to novel approaches to managing transplantation tolerance.
Tooth Restoration
Periodontal disease is a local inflammatory disease characterized by tissue and bone destruction, neutrophil infiltration, and lipid mediator activity. Hasturk et al. (p. 7021 ) analyzed the effects of treatment with Resolvin E1 (RvE1), an endogenous metabolite of an omega-3 polyunsaturated fatty acid, in a rabbit model of periodontal disease and found that this lipid could actively mediate inflammatory resolution. Rabbits with experimental periodontitis treated with RvE1 showed a dramatic resolution of clinical disease parameters and inflammation accompanied, surprisingly, by complete regeneration of bone and surrounding tissue. In contrast, treatment with the structurally similar lipids leukotriene B4 or prostaglandin E2 significantly exacerbated the disease and increased bone and tissue destruction. The disease-inducing organism, Porphyromonas gingivalis, persisted throughout the disease but was undetectable after RvE1 treatment. Finally, analysis of C-reactive protein and IL-1β in these animals demonstrated that periodontal disease induced systemic inflammation but that RvE1 treatment reduced the levels of these systemic mediators to near baseline levels. The ability of this endogenous mediator to rapidly restore normal tissue homeostasis may be applicable to the treatment of multiple diseases involving local inflammation.
Memory Requires Costimulation
Costimulation via CD28 is known to be required for the initiation of a T cell response; however, such costimulation is thought to be dispensable for memory T cell reactivation. Unexpectedly, Borowski et al. (p. 6494 ) found that CD8+ memory T cells required costimulation through CD28 to be reactivated in the context of viral infection. Mice treated with a blocking anti-CD28 Ab during secondary viral infection demonstrated significantly reduced numbers of activated CD8+ T cells and impaired viral clearance compared with untreated mice. Additionally, the authors transferred virus-specific memory CD8+ T cells into B7-deficient or wild-type mice and then challenged them with either influenza virus or HSV-1. Compared with wild-type mice, B7-deficient mice demonstrated decreased CD8+ T cell expansion and viral clearance, further supporting the importance of CD28 costimulation in memory cell activation. It was determined that the inhibition of CD8+ T cell activation occurred independently of CD4+ T cell help and involved up-regulation of the antiapoptotic molecule Bcl-2, with a corresponding arrest in the cell cycle. These data contradict current dogma regarding T cell costimulation requirements and may change our view of how T cell responses occur in vivo.
Anti-Tumor Teamwork
In addition to their role in early tumor immunosurveillance, NK cells have been proposed to act as a “fail-safe” mechanism to lyse tumor cells that escape CTL attack. Shanker et al. (p. 6651 ) undertook a comprehensive analysis of the abilities of tumor Ag-specific CD8+ T cells to reject a mastocytoma and discovered that these T cells provided necessary “help” to tumor-lysing NK cells. TCR-transgenic CD8+ T cells specific for the tumor Ag P1A could selectively reject P1A-expressing P815 tumors in RAG−/− mice even when injected into mice bearing established tumors. Gene expression analysis demonstrated that the P1A-specific CD8+ T cells were first activated in tumor-draining lymph nodes, after which they migrated to the tumor and were locally reactivated. However, during tumor growth, cells lacking the P1A epitope emerged but could be lysed by NK cells if P1A-specific CD8+ T cells were present before solid tumor establishment. Tumor cells lacking P1A were only lysed within a P1A+ tumor, and the lysis did not occur in mice depleted of NK cells. These data indicated that P1A-specific CD8+ T cells in the tumor provided help to tumor-infiltrating NK cells, modulating them into an effector phenotype that could then lyse cells lacking the T cell epitope. This study suggests that cooperation between innate immune effector cells and tumor-specific adaptive immune cells can lead to the elimination of tumors before metastasis.
Understanding IL-17
The proinflammatory cytokine IL-17A has recently been recognized as belonging to a larger family of related cytokines named IL-17A-F. Although IL-17A is known to play a crucial role in the development of collagen-induced arthritis (CIA), the function of other IL-17 family members remains under investigation. Yamaguchi et al. (p. 7128 ) therefore investigated the roles of IL-17B and IL-17C in CIA. Within arthritic joints, all IL-17 family members were elevated with IL-17A, IL-17C, and IL-17F expressed in CD4+ T cells and IL-17B in the cartilage. All of these molecules could induce proinflammatory cytokines, including IL-1β, TNF-α, IL-23, and in some cases IL-6, from fibroblasts and macrophages in vitro. Moreover, adoptively transferred CD4+ T cells transduced with any IL-17 family member exacerbated CIA progression in vivo. The IL-17 receptors IL-17Rh1 and IL-17R were also found to be elevated in arthritic joints. Development of bone marrow chimeras systemically expressing individual IL-17 family members supported the proinflammatory role of all of these cytokines through exacerbation of CIA, although IL-17A and F hastened disease onset whereas IL-17B and C did not. Overexpression of IL-17C led to spontaneous induction of TNF-α, and immunized IL-17B and IL-17C-expressing mice showed up-regulation of multiple inflammatory cytokines compared with controls. Interestingly, IL-17B blockade in wild-type mice suppressed CIA progression. Taken together, these data indicate that IL-17B and IL-17C are crucial in the effector phase of arthritis and that the IL-17 family of cytokines influences all stages of disease.
Summaries written by Jennifer Hartt Meyers, Ph.D.
- Copyright © 2007 by The American Association of Immunologists
