Heat shock protein 60 activates cytokine-associated negative regulator suppressor of cytokine signaling 3 in T cells: effects on signaling, chemotaxis, and inflammation

Previously, we reported that treatment of T cells with the 60-kDa heat shock protein (HSP60) inhibits chemotaxis. We now report that treatment of purified human T cells with recombinant human HSP60 or its biologically active peptide p277 up-regulates suppressor of cytokine signaling (SOCS)3 expression via TLR2 and STAT3 activation. SOCS3, in turn, inhibits the downstream effects of stromal cell-derived-1alpha (CXCL12)-CXCR4 interaction in: 1) phosphorylation of ERK1/2, Pyk2, AKT, and myosin L chain, required for cell adhesion and migration; 2) formation of rear-front T cell polarity; and 3) migration into the bone marrow of NOD/SCID mice. HSP60 also activates SOCS3 in mouse lymphocytes and inhibits their chemotaxis toward stromal cell-derived factor-1alpha and their ability to adoptively transfer delayed-type hypersensitivity. These effects of HSP60 could not be attributed to LPS or LPS-associated lipoprotein contamination. Thus, HSP60 can regulate T cell-mediated inflammation via specific signal transduction and SOCS3 activation.     

Histamine releasing factor and elongation factor 1 alpha secreted via malaria parasites extracellular vesicles promote immune evasion by inhibiting specific T cell responses

Protozoan pathogens secrete nanosized particles called extracellular vesicles (EVs) to facilitate their survival and chronic infection. Here, we show the inhibition by Plasmodium berghei NK65 blood stage‐derived EVs of the proliferative response of CD4⁺ T cells in response to antigen presentation. Importantly, these results were confirmed in vivo by the capacity of EVs to diminish the ovalbumin‐specific delayed type hypersensitivity response. We identified two proteins associated with EVs, the histamine releasing factor (HRF) and the elongation factor 1α (EF‐1α) that were found to have immunosuppressive activities. Interestingly, in contrast to WT parasites, EVs from genetically HRF‐ and EF‐1α‐deficient parasites failed to inhibit T cell responses in vitro and in vivo. At the level of T cells, we demonstrated that EVs from WT parasites dephosphorylate key molecules (PLCγ1, Akt, and ERK) of the T cell receptor signalling cascade. Remarkably, immunisation with EF‐1α alone or in combination with HRF conferred a long‐lasting antiparasite protection and immune memory. In conclusion, we identified a new mechanism by which P. berghei‐derived EVs exert their immunosuppressive functions by altering T cell responses. The identification of two highly conserved immune suppressive factors offers new conceptual strategies to overcome EV‐mediated immune suppression in malaria‐infected individuals.     

Inter-Subunit Interactions across the Upper Voltage Sensing-Pore Domain Interface Contribute to the Concerted Pore Opening Transition of Kv Channels

The tight electro-mechanical coupling between the voltage-sensing and pore domains of Kv channels lies at the heart of their fundamental roles in electrical signaling. Structural data have identified two voltage sensor pore inter-domain interaction surfaces, thus providing a framework to explain the molecular basis for the tight coupling of these domains. While the contribution of the intra-subunit lower domain interface to the electro-mechanical coupling that underlies channel opening is relatively well understood, the contribution of the inter-subunit upper interface to channel gating is not yet clear. Relying on energy perturbation and thermodynamic coupling analyses of tandem-dimeric Shaker Kv channels, we show that mutation of upper interface residues from both sides of the voltage sensor-pore domain interface stabilizes the closed channel state. These mutations, however, do not affect slow inactivation gating. We, moreover, find that upper interface residues form a network of state-dependent interactions that stabilize the open channel state. Finally, we note that the observed residue interaction network does not change during slow inactivation gating. The upper voltage sensing-pore interaction surface thus only undergoes conformational rearrangements during channel activation gating. We suggest that inter-subunit interactions across the upper domain interface mediate allosteric communication between channel subunits that contributes to the concerted nature of the late pore opening transition of Kv channels.     

The effects of temporal variation in soil carbon inputs on resource allocation in an annual plant

Aims Resource allocation in plants can be strongly affected by competition. Besides plant–plant interactions, terrestrial plants compete with the soil bacterial community over nutrients. Since the bacterial communities cannot synthesize their own energy sources, they are dependent on external carbon sources. Unlike the effect of overall amounts of carbon (added to the soil) on plant performance, the effect of fine scale temporal variation in soil carbon inputs on the bacterial biomass and its cascading effects on plant growth are largely unknown. We hypothesize that continuous carbon supply (small temporal variance) will result in a relatively constant bacterial biomass that will effectively compete with plants for nutrients. On the other hand, carbon pulses (large temporal variance) are expected to cause oscillations in bacterial biomass, enabling plants temporal escape from competition and possibly enabling increased growth. We thus predicted that continuous carbon supply would increase root allocation at the expense of decreased reproductive output. We also expected this effect to be noticeable only when sufficient nutrients were present in the soil.Methods Wheat plants were grown for 64 days in pots containing either sterilized or inoculated soils, with or without slow-release fertilizer, subjected to one of the following six carbon treatments: daily (1.5mg glucose), every other day (3mg glucose), 4 days (6mg glucose), 8 days (12mg glucose), 16 days (24mg glucose) and no carbon control.Important findings Remarkably, carbon pulses (every 2–16 days) led to increased reproductive allocation at the expense of decreased root allocation in plants growing in inoculated soils. Consistent with our prediction, these effects were noticeable only when sufficient nutrients were present in the soil. Furthermore, soil inoculation in plants subjected to low nutrient availability resulted in decreased total plant biomass. We interpret this to mean that when the amount of available nutrients is low, these nutrients are mainly used by the bacterial community. Our results show that temporal variation in soil carbon inputs may play an important role in aboveground–belowground interactions, affecting plant resource allocation.     

Comparative oogenesis in cardinal fishes (Apogonidae,Perciformes), with special focus on the adaptive structures of the egg envelopes

The present study compares gonad structure and oogenesis in 30 species of cardinal fish (Apogonidae) from the Indo-Pacific region. In all of the species studied the ovaries are bilobed, with each lobe possessing ovigerous lamellae whose numbers and dimensions increase concomitantly with growth of the fish and reproductive stage, and correlate with the total dimensions of the particular species. In species of the genus Siphamia, the ovarian lobes are associated with a fat body that is not found in species of the other genera studied. Some of the species studied (Siphamia spp.; Archamia spp.) demonstrate group-synchronized maturation of eggs, possibly with only one spawn per reproduction season. However, most of the Apogon spp., and other genera, have unsynchronized cycles, a characteristic of multiple spawners. The various stages of previtellogenic and vitellogenic development are similar in the different species, but differ in timing and dimensions of the oocytes around which the morphogenesis of the egg envelope (chorion) and follicle begins. Differentiation of the egg envelope and follicle cells parallels the vitellogenic stages of egg development. The number of eggs was found to correlate positively with the length of the body and ovary of the fish, whereas egg diameter was found to correlate negatively with body length. The surface of the egg envelope bears ridges that form patterns of various types, whose structures and dimensions seem to be species-specific, and which in most species converge upon the single micropyle on the animal pole. The exposed ridge mazes include a special fibrous web that anchors in the micropyle. The production and importance of these ridges, as well as the correlations between egg numbers per spawn, egg dimensions, and the oral dimensions of the paternal male, are discussed.