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Age-dependent changes in their environment can impair stem cells' function. The finding that T cells infiltrate the brains of aged mice and cause dysfunction of neural stem cells reveals a potential therapeutic target. Immune cells enter ageing mouse brains and hinder nerve-cell production., Author(s): Allison M. Bond, Hongjun Song Author Affiliations: Infiltration of old brains by T cells causes dysfunction of neural stem cells In a healthy adult, tissue-specific stem cells replenish damaged [...]

Cerebral malaria is a significant cause of global mortality, causing an estimated two million deaths per year, mainly in children. The pathogenesis of this disease remains incompletely understood. Chemokines have been implicated in the development of cerebral malaria, and the IFN-inducible CXCR3 chemokine ligand IP-10 (CXCL10) was recently found to be the only serum biomarker that predicted cerebral malaria mortality in Ghanaian children. We show that the CXCR3 chemokine ligands IP-10 and Mig (CXCL9) were highly induced in the brains of mice with murine cerebral malaria caused by Plasmodium berghei ANKA. Mice deficient in CXCR3 were markedly protected against cerebral malaria and had far fewer T cells in the brain compared with wild-type mice. In competitive transfer experiments, CXCR3-deficient CD[8.sup.+] T cells were 7-fold less efficient at migrating into the infected brains than wild-type CD[8.sup.+] T cells. Adoptive transfer of wild-type CD[8.sup.+] effector T cells restored susceptibility of CXCR3-deficient mice to cerebral malaria and also restored brain proinflammatory cytokine and chemokine production and recruitment of T cells, independent of CXCR3. Mice deficient in IP-10 or Mig were both partially protected against cerebral malaria mortality when infected with P. berghei ANKA. Brain immunohistochemistry revealed Mig staining of endothelial cells, whereas IP-10 staining was mainly found in neurons. These data demonstrate that CXCR3 on CD[8.sup.+] T cells is required for T cell recruitment into the brain and the development of murine cerebral malaria and suggest that the CXCR3 ligands Mig and IP-10 play distinct, nonredundant roles in the pathogenesis of this disease. T cells | Plasmodium | IP-10 | brain | trafficking

T helper 1 (Th1) cells mediate powerful cellular immune responses. However, if unbalanced, Th1 immunity eventually may cause pathology. Recently, it has been shown that IL-10, an antiinflammatory cytokine strongly antagonizing Th1-mediated effects, can be produced by Th1 cells and is indeed essential for self-regulation of Th1 immunity. Here, we show that Notch induces IL-10 production in newly developing and already established Th1 cells via a signal transducer and activator of transcription 4 (STAT4)-dependent process. Notch signaling in the presence of the cytokines IL-12 or IL-27 induces Th1 cells to produce large amounts of IL-10 without diminishing IFN-[gamma] production. Notch-modified Thl cells completely lose their inflammatory capacity and instead are able to actively suppress a Th1 cell-induced delayed-type hypersensitivity (DTH) reaction in an IL-10-dependent fashion. IL-10 production can be elicited by active forms of all four mammalian Notch receptors but was found to be specific for the Delta-like family of Notch ligands. Dendritic cells (DC) selectively acquire Delta-like 4 expression upon stimulation with various Toll-like receptor (TLR) ligands and concomitantly induce IL-10 production by Th1 cells in vitro and in vivo. This effect can be selectively reversed by pharmacological inhibitots of Notch signaling ([gamma]-secretase inhibitor). Our data suggest that Notch regulates IL-10 production in Th1 cells by a STAT4-dependent process that converts proinflammatory Th1 cells into T cells with regulatory activity. This pathway may provide unique opportunities for therapeutic intervention in Th1-driven immune diseases and for Th1-associated vaccination strategies. immunoregulation | inflammation | Notch signaling IT helper differentiation | T regulatory 1 cells

Antigen-specific transplantation tolerance in the absence of immunosuppressive drugs is a rarely achieved goal. Immune responses to Y chromosome-encoded transplantation antigens (HY) can have life-threatening consequences in the clinic. Here, we have adopted a procedure developed in T cell antigen receptor (TCR)-transgenic mice to convert naive T cells into male-specific [Foxp3.sup.+] regulatory T cells (Tregs) in WT female mice. For this purpose, female mice were infused by osmotic minipumps with a single class II MHC-presented HY peptide and Tregs visualized by tetramer staining. As a result, animals developed Treg-mediated long-term tolerance to all HY transplantation antigens, irrespective of whether they were recognized by CD4 or CD8 T cells, on skin or hematopoietic grafts from male donors. Foxp3 | induction of tolerance | transplantation tolerance

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD[8.sup.+] effector T cells to FoxP[3.sup.+] regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy. CTLA-4 | regulatory T cells (Tregs) | vaccine | GM-CSF

[CD4.sup.+] Th1 type immunity is implicated in resistance to global infectious diseases. To improve the efficacy of T cell immunity induced by human immunodeficiency virus (HIV) vaccines, we are developing a protein-based approach that directly harnesses the function of dendritic cells (DCs) in intact lymphoid tissues. Vaccine proteins are selectively delivered to DCs by antibodies to DEC-205/ CD205, a receptor for antigen presentation. We find that polyriboinosinic-polyribocytidylic acid (poly IC) independently serves as an adjuvant to allow a DC-targeted protein to induce protective [CD4.sup.+] T cell responses at a mucosal surface, the airway. After two doses of DEC-targeted, HIV gag p24 along with poly IC, responder [CD4.sup.+] T cells have qualitative features that have been correlated with protective function. The T cells simultaneously make IFN-[gamma] tumor necrosis factor (TNF)-[alpha], and IL-2, and in high amounts for prolonged periods. The T cells also proliferate and continue to secrete IFN-y in response to HIV gag p24. The adjuvant role of poly IC requires Toll-like receptor (TLR) 3 and melanoma differentiation-associated gene-5 (MDA5) receptors, but its analog poly [IC.sub.12]U requires only TLR3. We suggest that poly IC be tested as an adjuvant with DC-targeted vaccines to induce numerous multifunctional [CD4.sup.+] Thl cells with proliferative capacity. HIV | gag | adjuvant | MDA5 | TLR3

The molecular mechanisms used by regulatory T cells (Treg) to inhibit the effector phase of adaptive immune responses are still elusive. In the present work, we investigated the possibility that Treg may interfere with a basic biological function of T helper ceils ([T.sub.H]): polarization of secretory machinery for dedicated help delivery. To address this question, we visualized by confocal microscopy different parameters of activation in TH and Treg ceils interacting simultaneously with individual antigen-presenting cells (APC). Our results show that, although productive TCR engagement in [T.sub.H]/APC conjugates was unaffected by the presence of adjacent Treg, the reorientation of [T.sub.H] secretory machinery toward APC was strongly inhibited. Blocking TGF-[beta] completely reverted Treg induced inhibition of [T.sub.H] polarization. Our results identify a previously undescribed mechanism by which Treg inhibit effector T cells. TGF-[beta] produced by adjacent Treg interferes with polarization of [T.sub.H] secretory machinery toward APC, thus affecting a crucial step of [T.sub.H]-mediated amplification of the immune response. confocal microscopy | immunological synapse | T cell activation

The danger theory of immune tolerance asserts that environmental factors hold primacy over lymphocyte autoreactivity in initiating autoimmune disease. We sought to test this contention using the Aire-deficient mouse model of the human disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, a multiorgan autoimmune disorder rooted in a lesion in thymic tolerance. Compound screens stimulating a broad range of innate immune system pathways failed to show any modulation of disease characteristics in [Aire.sup.-/-] mice on either the C57BL/6 or NOD genetic backgrounds. Furthermore, deficiency in the Toll-like receptor adaptor Myd88 increased the lifespan of [NOD.aire.sup.-/-] mice but did not prevent the initiation of autoimmunity. Finally, germ-free NOD. [aire.sup.-/-] mice exhibited autoimmunity in all organs normally targeted in this model, indicating that microbial conditioning is not required for activation of autoreactive T cells relevant to this disease. Together, these data suggest that the stochastic genesis of dangerous T cell clones can initiate autoimmune disease without the need for environmental stimulation, underlining the importance of Aire-dependent thymic deletion. autoimmunity | environment | immunological tolerance

T cells have been implicated in the pathogenesis of renal ischemia-reperfusion injury (IRI). To date existing data about the role of the T cell receptor (Tcr) are contradictory. We hypothesize that the Tcr plays a prominent role in the late phase of renal IRI. Therefore, renal IRI was induced in [alpha]/[beta], [gamma]/[delta] T cell-deficient and wild-type mice by clamping renal pedicles for 30 min and reperfusing for 24, 48, 72, and 120 h. Serum creatinine increased equally in all three groups 24 h after ischemia but significantly improved in Tcr-deficient animals compared with wildtype controls after 72 h. A significant reduction in renal tubular injury and infiltration of CD[4.sup.-] T-cells in both Tcr-deficient mice compared with wild-type controls was detected. Infiltration of [alpha]/[beta] T cells into the kidney was reduced in [gamma]/[delta] T cell-deficient mice until 72 h after ischemia. In contrast, [gamma]/[delta] T cell infiltration was equal in wild-type and [alpha]/[beta] T cell-deficient mice, suggesting an interaction between [alpha]/[beta] and [gamma]/[delta] T cells. Data from [gamma]/[delta] T cell-deficient mice were confirmed by in vivo depletion of [gamma]/[delta] T cells in C57BL/6 mice. Whereas [alpha]/[beta] T cell-deficient mice were still protected after 120 h, [gamma]/[delta] T cell-deficient mice showed a 'delayed wild-type phenotype' with a dramatic increase in kidney-infiltrating [alpha]/[beta], Tcr-expressing CD[4.sup.+] T-cells. This report provides further evidence that [alpha]/[beta] T cells are major effector cells in renal IRI, whereas [gamma]/[delta] T cells play a role as mediator cells in the first 72 h of renal IRI. inflammation; acute renal failure

Researches on mice with no alpha-beta or gamma-delta T cells and infected with listeria monocytogenes revealed that secondary infection resistance is primarily due to alpha-beta T cells. Abnormal lever lesions were observed in infected mice with deficiency in gamma-delta T cells. Either alpha-beta or gamma-delta T cells are adequate for initial protection against primary listeriosis. The formation of granulomatous lesions is determined by the alpha-beta T cell subset.