Liver-Primed Memory T Cells Generated under Noninflammatory Conditions Provide Anti-infectious Immunity

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Highlights? Memory-like CD8⁺ T cells are generated in the liver in the absence of inflammation ? An alternative pathway of T cell priming is facilitated by nonimmune cells ? Liver-primed T cells are rescued from deletion for anti-infectious immunity ? T cell priming in the liver complements conventional memory T cell generation     

Induction of pro-inflammatory mediators in Plasmodium berghei infected BALB/c mice breaks blood-brain-barrier and leads to cerebral malaria in an IL-12 dependent manner

A severe complication of Plasmodium infection is cerebral malaria, a condition mainly attributed to overwhelming inflammatory immune reactions of the host. Murine models differing in susceptibility to experimental cerebral malaria (ECM) allow detailed studies of the host response. We show that ECM- resistant BALB/c mice were driven into interferon gamma- and IL-12-dependent ECM and subsequent death if they received CpG-oligonucleotides after Plasmodium berghei ANKA (PbA) infection. CpG application triggered production of pro-inflammatory cytokines systemically as well in spleen and brain and induced neuropathological symptoms, leading to increased mortality. Experiments with genetically deficient mice confirmed the role of IFN-γ and IL-12 during CpG-triggered immunopathology. Furthermore, the application of CpG and downstream production of pro-inflammatory cytokines contributed to the break down of the blood brain barrier visualized by Evan's Blue, comparable to PbA-infected C57BL/6 mice. Taken together, resistance of BALB/c mice towards ECM development could be altered through induction of pro-inflammatory cytokines by CpG. Therefore, approaches discussed earlier to induce pro-inflammatory immune reactions for malaria protection should be considered with caution.     

Activation of protein kinase B/Akt by alpha1-adrenoceptors in the human prostate

AimsBesides their role in contraction, α1-adrenoceptors may be involved in prostate hyperplasia. This would require receptor signaling by growth-promoting pathways. Akt (syn. Protein kinase B) is an important regulator of growth and differentiation. Objective: To investigate whether α1-adrenoceptors in the human prostate activate Akt.Main methodsProstate tissue was obtained from patients undergoing radical prostatectomy. Akt expression was investigated by RT-PCR, Western blot, and immunohistochemistry. Akt activation by noradrenaline (30 μM) and phenylephrine (10 μM) was assessed by Western blot analyses with a phospho-specific antibody. The effects of the Akt inhibitors FPA-124 and 10-DEBC on phenylephrine-, noradrenaline- and electric field stimulation- (EFS-) induced contraction were studied in myographic measurements.Key findingsmRNA of all three Akt isoforms (Akt1, Akt2, Akt3) was detected by RT-PCR in all prostate samples (n = 6 patients). Protein expression was confirmed by Western blot analysis (n = 8 patients). Immunohistochemical staining for Akt revealed strong immunoreactivity in prostate smooth muscle cells (n = 5 patients). Stimulation of prostate tissues with noradrenaline (30 μM, n = 8 patients) or phenylephrine (10 μM, n = 7 patients) caused significant Akt phosphorylation at serine-473, indicating activation of Akt. FPA124 and 10-DEBC were without effects on noradrenaline-, phenylephrine-, or EFS-induced contraction of prostate strips.SignificanceProstate α1-adrenoceptors activate Akt. Consequently, Akt is a target of α1-blocker therapy, which has been unknown to date. Our findings point to functions of prostate α1-adrenoceptors besides contraction.     

CCR2 mediates homeostatic and inflammatory release of Gr1(high) monocytes from the bone marrow, but is dispensable for bladder infiltration in bacterial urinary tract infection

CCR2 is thought to recruit monocytes to sites of infection. Two subpopulations of murine blood monocytes differing in Gr1 and CCR2 expression have been described. The exact role of CCR2 in migration of CCR2(low)Gr1(low) and CCR2(high)Gr1(high) monocytes into nonlymphoid tissue is controversial. In this study, we have addressed this question in a murine model of bacterial urinary tract infection. Only Gr1(high) monocytes were recruited into the infected bladder. CCR2 deficiency reduced their frequency in this organ, indicating a requirement of this chemokine receptor. Importantly, CCR2-deficient mice also showed reduced Gr1(high) monocyte numbers in the blood, but not in the bone marrow (BM), indicating that CCR2 acted at the step of monocyte release into the circulation. The same was found also in noninfected mice, indicating a further involvement of CCR2 in steady-state BM egress. An additional requirement of CCR2 in monocyte recruitment from the blood into the bladder was excluded by tracking particle-labeled endogenous monocytes and by adoptive transfer of BM-derived monocyte subsets. These findings demonstrate that CCR2 governs homeostatic and infection-triggered release of Gr1(high) monocytes from the BM into the blood but is dispensable for recruitment into a nonlymphoid tissue.     

Specific Depletion of Ly6Chi Inflammatory Monocytes Prevents Immunopathology in Experimental Cerebral Malaria

Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice leads to experimental cerebral malaria (ECM) that is commonly associated with serious T cell mediated damage. In other parasitic infection models, inflammatory monocytes have been shown to regulate Th1 responses but their role in ECM remains poorly defined, whereas neutrophils are reported to contribute to ECM immune pathology. Making use of the recent development of specific monoclonal antibodies (mAb), we depleted in vivo Ly6C^hi inflammatory monocytes (by anti-CCR2), Ly6G⁺ neutrophils (by anti-Ly6G) or both cell types (by anti-Gr1) during infection with Ovalbumin-transgenic PbA parasites (PbTg). Notably, the application of anti-Gr1 or anti-CCR2 but not anti-Ly6G antibodies into PbTg-infected mice prevented ECM development. In addition, depletion of Ly6C^hi inflammatory monocytes but not neutrophils led to decreased IFNγ levels and IFNγ⁺CD8⁺ T effector cells in the brain. Importantly, anti-CCR2 mAb injection did not prevent the generation of PbTg-specific T cell responses in the periphery, whereas anti-Gr1 mAb injection strongly diminished T cell frequencies and CTL responses. In conclusion, the specific depletion of Ly6C^hi inflammatory monocytes attenuated brain inflammation and immune cell recruitment to the CNS, which prevented ECM following Plasmodium infection, pointing out a substantial role of Ly6C⁺ monocytes in ECM inflammatory processes.     

Transfer of T cell surface molecules to dendritic cells upon CD4+ T cell priming involves two distinct mechanisms

Activation of CD4(+) T cells by APCs occurs by multiple Ag recognition events including the exchange of costimulatory signals and cytokines. Additionally, the T cells acquire APC-derived surface molecules. Herein, we describe for the first time the transfer of human and murine T cell surface receptors to APCs after Ag-specific interaction. This transfer occurs in two qualitatively different phases. The first group of molecules (e.g., CD2) derived from the T cell surface was transferred rapidly after 2 h of interaction, was strongly bound on the DC surface (acid wash-resistant), was strictly dependent on dendritic cell-T cell contact, and transferred independently of T cell activation. The second group, including the CD3/TCR complex, CD27, and OX40, was of intracellular origin, transferred later after 10-16 h in a cell-cell contact-independent fashion, was noncovalently bound, and was strictly dependent on Ag-specific T cell activation. Functionally, murine dendritic cells that received TCR molecules from OVA-specific CD4(+) T cells after Ag-specific interaction were less efficient in priming naive CD4(+) T cells of the same specificity without losing their ability for CD8(+) T cell stimulation, indicating that the transferred TCR molecules mask the Ag-bearing MHC II molecules, thereby reducing their accessibility to following Ag-specific CD4(+) T cells. While the first group of transferred T cell surface molecules might facilitate the detachment of the CD4(+) T cell from the dendritic cell during the early scanning phases, the second group could play an important immunomodulatory role in intraclonal competition of T cells for APC access, making the physical presence of CD4(+) T cells unnecessary.     

The role of small molecules in restricting rice accumulation of dimethylarsinic acid

Plant and Soil - Dimethylarsinic acid (DMA), an organic arsenic compound found in rice grain, is a causal agent of straighthead disorder, which can decimate yields. To minimize rice accumulation of...     

Bone marrow as a priming site for T-cell responses to blood-borne antigen

Although bone marrow is known as a primary lymphoid organ, its potential to serve as a secondary immune organ has hardly been explored. Here we demonstrate that naive, antigen-specific T cells home to bone marrow, where they can be primed. Antigen presentation to T cells in bone marrow is mediated via resident CD11c+ dendritic cells. They are highly efficient in taking up exogenous blood-borne antigen and processing it via major histocompatibility complex class I and class II pathways. T-cell activation correlates with dendritic cell-T cell clustering in bone marrow stroma. Primary CD4+ and CD8+ T-cell responses generated in bone marrow occur in the absence of secondary lymphoid organs. The responses are not tolerogenic and result in generation of cytotoxic T cells, protective anti-tumor immunity and immunological memory. These findings highlight the uniqueness of bone marrow as an organ important for hemato- and lymphopoiesis and for systemic T cell-mediated immunity.