Amiloride-sensitive and amiloride-insensitive responses to NaCl + acid mixtures in hamster chorda tympani nerve

Component signaling in taste mixtures containing both beneficial and dangerous chemicals depends on peripheral processing. Unidirectional mixture suppression of chorda tympani (CT) nerve responses to sucrose by quinine and acid is documented for golden hamsters (Mesocricetus auratus). To investigate mixtures of NaCl and acids, we recorded multifiber responses to 50 mM NaCl, 1 and 3 mM citric acid and acetic acid, 250 μM citric acid, 20 mM acetic acid, and all binary combinations of each acid with NaCl (with and without 30 μM amiloride added). By blocking epithelial Na(+) channels, amiloride treatment separated amiloride-sensitive NaCl-specific responses from amiloride-insensitive electrolyte-generalist responses, which encompass all of the CT response to the acids as well as responses to NaCl. Like CT sucrose responses, the amiloride-sensitive NaCl responses were suppressed by as much as 50% by citric acid (P = 0.001). The amiloride-insensitive electrolyte-generalist responses to NaCl + acid mixtures approximated the sum of NaCl and acid component responses. Thus, although NaCl-specific responses to NaCl were weakened in NaCl-acid mixtures, electrolyte-generalist responses to acid and NaCl, which tastes KCl-like, were transmitted undiminished in intensity to the central nervous system. The 2 distinct CT pathways are consistent with known rodent behavioral discriminations.     

Full-breadth analysis of CD8+ T-cell responses in acute hepatitis C virus infection and early therapy

Multispecific CD8(+) T-cell responses are thought to be important for the control of acute hepatitis C virus (HCV) infection, but to date little information is actually available on the breadth of responses at early time points. Additionally, the influence of early therapy on these responses and their relationships to outcome are controversial. To investigate this issue, we performed comprehensive analysis of the breadth and frequencies of virus-specific CD8(+) T-cell responses on the single epitope level in eight acutely infected individuals who were all started on early therapy. During the acute phase, responses against up to five peptides were identified. During therapy, CD8(+) T-cell responses decreased rather than increased as virus was controlled, and no new specificities emerged. A sustained virological response following completion of treatment was independent of CD8(+) T-cell responses, as well as CD4(+) T-cell responses. Rapid recrudescence also occurred despite broad CD8(+) T-cell responses. Importantly, in vivo suppression of CD3(+) T cells using OKT3 in one subject did not result in recurrence of viremia. These data suggest that broad CD8(+) T-cell responses alone may be insufficient to contain HCV replication, and also that early therapy is effective independent of such responses.     

Development of tectum-striatum and striatum-tectum connections in the chick]

In the chick, polyphasic evoked responses displaying a first negative component have been registered in the superficial part of the "Wulst" after stimulation in the depth of the contra or ipsilateral optic tectum, as early as the first hours following hatching. Moreover, responses on the surface of the tectum have been elicited by contra or ipsilateral stimulation of the Wulst. Latencies of both responses decrease markedly with increasing age but, in the whole, ipsilateral responses remain more latent than contralateral responses.     

Contractile function of vessel myocytes: dependence on the stretch magnitude]

The values of the optimal stretch for the maximal responses of the rat mesenteric artery ring to electrical field stimulation (FES) or noradrenaline as well as for the maximal myogenic responses, tone, and maximal changes in these responses produced by low pH and dynamic sinusoidal stretch of the vessel wall were compared. The findings show that the magnitude of stretch corresponding to the maximal effect depend on the character of responses, on the factor, and on the responses occurrence conditions.     

Observations on bioluminescence in some deep-water anthozoans

The luminous responses to electrical stimulation of isolated polyps of 4 deep-water anthozoans are described. All show facilitatory responses and summation at stimulus frequencies > 2 s^–1. The responses of the gorgonian Acanella arbuscula comprise a slow summation of weak individual flashes. It is suggested that there is no fundamental difference between deep and shallow species, nor between the responses of scyphozoans, such as Pelagia and Atolla, and anthozoans, such as those described here. Both facilitated and decremental responses can be obtained from each of the 2 groups and the complexity of in vivo responses may be as much a reflection of selective pressures on the neural pathways as on the bioluminescent systems themselves.     

Differential sensitivity to rotation measured on potentials evoked by electrical stimulation of the guinea-pig ear

Responses to electrical stimulation of the ear applied between round-window and vertex electrodes were recorded in awake guinea-pigs from the same electrodes or from separate vertex/mastoid subdermal needle electrodes. They were averaged during opposite phases of sinusoidal rotation or before and after constant velocity rotation. In both cases the responses were subtracted from each other and yielded differential per- or post-rotatory “electrovestibular” responses. For comparison, responses were also recorded in the same animals and conditions of electrical stimulation during silence and during presentation of a broad-band noise. The difference yielded “electroacoustic” responses. In round-window records, electrovestibular and electroacoustic responses presented typical compound nerve action potential patterns. Electrovestibular responses could be recorded for head angular velocities as low as 3° sec⁻¹ at 0.1 Hz. Response amplitude showed a logarithmic relation to head velocity. Changes in amplitude, as a function of time after rotation, were comparable to those reported for vestibular nerve fibre responses. In vertex/mastoid records, electroacoustic responses presented a sequence of peaks similar to the click-evoked auditory brain-stem responses, and electrovestibular responses presented two peaks, presumably representing contributions of central vestibular structures. Such “electrovestibulography” permits the study of an individual ear and makes available to the investigator a large range of vestibular stimulation conditions.     

Human immunodeficiency virus (HIV)-specific gamma interferon secretion directed against all expressed HIV genes: relationship to rate of CD4 decline

Immune responses to human immunodeficiency virus (HIV) are detected at all stages of infection and are believed to be responsible for controlling viremia. This study seeks to determine whether gamma interferon (IFN-gamma)-secreting HIV-specific T-cell responses influence disease progression as defined by the rate of CD4 decline. The study population consisted of 31 subjects naive to antiretroviral therapy. All were monitored clinically for a median of 24 months after the time they were tested for HIV-specific responses. The rate of CD4+-T-cell loss was calculated for all participants from monthly CD4 counts. Within this population, 17 subjects were classified as typical progressors, 6 subjects were classified as fast progressors, and 8 subjects were classified as slow progressors. Peripheral blood mononuclear cells were screened for HIV-specific IFN-gamma responses to all expressed HIV genes. Among the detected immune responses, 48% of the recognized peptides were encoded by Gag and 19% were encoded by Nef gene products. Neither the breadth nor the magnitude of HIV-specific responses correlated with the viral load or rate of CD4 decline. The breadth and magnitude of HIV-specific responses did not differ significantly among typical, fast, and slow progressors. These results support the conclusion that although diverse HIV-specific IFN-gamma-secreting responses are mounted during the asymptomatic phase, these responses do not seem to modulate disease progression rates.     

Interleukin 2 induction of antigen-nonspecific suppressor cells

Although Interleukin 2 (IL-2) is essential to the generation of immune responses it may also be important as a regulator of these same responses, as both primary and secondary anti-SRBC responses are greatly diminished when IL-2 is included in culture. IL-2 must be present within the first 24 hr of culture to affect maximum suppression. This inhibition is mediated by suppressor cells which are expanded by pulsing spleen cells with IL-2 for 48-72 hr. Their development is not antigen dependent and their action is antigen nonspecific. Suppressor cell activity can be generated from either naive or primed animals which are equally effective in inhibiting primary or secondary anti-SRBC responses. Suppressor cells can be propagated for long periods of time in T-cell growth factor-containing medium. These long-term cultured cells retain the ability to inhibit various immune responses such as mitogen- and alloantigen-induced proliferation, the generation of cytotoxic T lymphocytes and humoral responses. These cells suppress these responses by absorbing IL-2, as demonstrated by their ability to remove IL-2 upon incubation at 4 degrees C, and the reversal of suppression by the addition of supraoptimal amounts of IL-2.     

Resilience vs. historical contingency in microbial responses to environmental change

How soil processes such as carbon cycling will respond to future climate change depends on the responses of complex microbial communities, but most ecosystem models assume that microbial functional responses are resilient and can be predicted from simple parameters such as biomass and temperature. Here, we consider how historical contingencies might alter those responses because function depends on prior conditions or biota. Functional resilience can be driven by physiological, community or adaptive shifts; historical contingencies can result from the influence of historical environments or a combination of priority effects and biotic resistance. By modelling microbial population responses to environmental change, we demonstrate that historical environments can constrain soil function with the degree of constraint depending on the magnitude of change in the context of the prior environment. For example microbial assemblages from more constant environments were more sensitive to change leading to poorer functional acclimatisation compared to microbial assemblages from more fluctuating environments. Such historical contingencies can lead to deviations from expected functional responses to climate change as well as local variability in those responses. Our results form a set of interrelated hypotheses regarding soil microbial responses to climate change that warrant future empirical attention.     

Transcutaneous immunization with cholera toxin B subunit adjuvant suppresses IgE antibody responses via selective induction of Th1 immune responses

Topical application of cholera toxin (CT) onto mouse skin can induce a humoral immune response to CT as well as to coadministered Ags. In this study, we examined the nontoxic cell-binding B subunit of CT (CTB) as a potential adjuvant for cutaneous immune responses when coadministered with the prototype protein Ag, OVA. CTB applied onto skin induced serum Ab responses to itself with magnitudes comparable to those evoked by CT but was poorly efficient at promoting systemic Ab responses to coadministered OVA. However, transcutaneous immunization (TCI) with either CT or CTB and OVA led to vigorous OVA-specific T cell proliferative responses. Furthermore, CTB potentiated Th1-driven responses (IFN-gamma production) whereas CT induced both Th1 and Th2 cytokine production. Coadministration of the toxic subunit CTA, together with CTB and OVA Ag, led to enhanced Th1 and Th2 responses. Moreover, whereas TCI with CT enhanced serum IgE responses to coadministered OVA, CTB suppressed these responses. TCI with either CT or CTB led to an increased accumulation of dendritic cells in the exposed epidermis and the underlying dermis. Thus, in contrast to CT, CTB appears to behave very differently when given by the transcutaneous as opposed to a mucosal route and the results suggest that the adjuvanticity of CT on Th1- and Th2-dependent responses induced by TCI involves two distinct moieties, the B and the A subunits, respectively.     

Preferential role for NF-kappa B/Rel signaling in the type 1 but not type 2 T cell-dependent immune response in vivo.

T cell function is a critical determinant of immune responses as well as susceptibility to allergic diseases. Activated T cells can differentiate into effectors whose cytokine profile is limited to type 1 (IFN-gamma-dominant) or type 2 (IL-4-, IL-5-dominant) patterns. To investigate mechanisms that connect extracellular stimuli with the regulation of effector T cell function, we have measured immune responses of transgenic mice whose NF-kappa B/Rel signaling pathway is inhibited in T cells. Surprisingly, these mice developed type 2 T cell-dependent responses (IgE and eosinophil recruitment) in a model of allergic pulmonary inflammation. In contrast, type 1 T cell responses were severely impaired, as evidenced by markedly diminished delayed-type hypersensitivity responses, IFN-gamma production, and Ag-specific IgG2a levels. Taken together, these data indicate that inhibition of NF-kappa B can lead to preferential impairment of type 1 as compared with type 2 T cell-dependent responses.     

Context-dependent effects of noise on echolocation pulse characteristics in free-tailed bats

Background noise evokes a similar suite of adaptations in the acoustic structure of communication calls across a diverse range of vertebrates. Echolocating bats may have evolved specialized vocal strategies for echolocating in noise, but also seem to exhibit generic vertebrate responses such as the ubiquitous Lombard response. We wondered how bats balance generic and echolocation-specific vocal responses to noise. To address this question, we first characterized the vocal responses of flying free-tailed bats (Tadarida brasiliensis) to broadband noises varying in amplitude. Secondly, we measured the bats’ responses to band-limited noises that varied in the extent of overlap with their echolocation pulse bandwidth. We hypothesized that the bats’ generic responses to noise would be graded proportionally with noise amplitude, total bandwidth and frequency content, and consequently that more selective responses to band-limited noise such as the jamming avoidance response could be explained by a linear decomposition of the response to broadband noise. Instead, the results showed that both the nature and the magnitude of the vocal responses varied with the acoustic structure of the outgoing pulse as well as non-linearly with noise parameters. We conclude that free-tailed bats utilize separate generic and specialized vocal responses to noise in a context-dependent fashion.     

IgM-mediated enhancement of in vivo anti-sheep erythrocyte antibody responses: isotype analysis of the enhanced responses

The direct splenic anti-sheep erythrocyte (anti-SRBC) responses as well as the serum IgG1, IgG2a, IgG2b, and IgG3 anti-SRBC responses of CBA/CaJ mice were monitored 4-35 days after immunization with: (1) a suboptimal dose of SRBC, (2) a suboptimal dose of SRBC plus monoclonal IgM anti-SRBC, or (3) a high dose of SRBC. The direct plaque-forming cell (PFC) responses of mice in treatment group 2 were significantly higher than those in group 1 but similar to the responses in group 3. The serum anti-SRBC antibody responses of all IgG subclasses were significantly enhanced by IgM anti-SRBC and were generally even higher than the responses obtained with high doses of SRBC. The relative proportions of each serum IgG subclass were similar in all three groups. These data suggest that the enhancement of suboptimal anti-SRBC antibody responses by IgM anti-SRBC extends through IgM and all of the IgG subclasses and, further, that the isotype profile in antibody-enhanced responses is similar to that obtained with high doses of SRBC.     

T cell recognition patterns of immunodominant cytomegalovirus antigens in primary and persistent infection

Replication of human cytomegalovirus is controlled by a vigorous CD8 T cell response. The persistent nature of infection is believed to periodically stimulate T cell responses resulting in considerable expansions of virus-specific CD8 T cells over time. In this study, we describe the magnitude and breadth of CD8 T cell responses against the immunodominant viral Ags, IE-1 and pp65, in acute and long-term infection using the IFN-gamma ELISPOT assay. Simultaneously, we have identified several novel MHC class I restricted CD8 T cell epitopes. Acute phase responses in immunocompetent donors appear to be extremely focused as early as 1 week post diagnosis with dominant peptide-specific responses observed against both proteins. These dominant responses remain detectable at all later time points over a 4-year follow-up. Interestingly the IE-1 responses show an increase over time whereas the pp65 responses do not, which contrasts with data showing that responses against both Ags are elevated in elderly individuals. We also observe the rapid emergence of an effector memory phenotype for virus-specific CD8 T cells as observed in persistent infection. Over time the revertant CD45RA(pos) effector cell population is also expanded, and this is more evident in the preferentially expanded IE-1 responses. We postulate that periodic low-level virus reactivation after the acute infection phase preferentially stimulates these responses whereas pp65-specific T cell expansions probably occur during the infrequent episodes of lytic viral replication or secondary infection.     

T cell-dependent hapten-specific and polyclonal B cell responses require release of interleukin 5

CD4+ T cells in the mouse have recently been subdivided into two major subpopulations which differ in their functional activities and in the lymphokines they produce. Although cloned T cells lines representative of both sets will activate B cells in polyclonal responses, only the subset producing interleukin 4 (IL-4) will activate antigen-specific B cells in linked recognition assays. This suggested that IL-4 was essential for such responses. In the present experiments, the requirements were compared for B cell activation in specific as opposed to polyclonal antibody responses by T cell clones of the helper (IL-4 producing) subset. It was found that specific responses involve primarily small B cells, whereas polyclonal responses activate exclusively the large B cells. Second, polyclonal B cell responses can proceed in the absence of T:B contact, whereas specific responses require physical interaction of the two cells. Third, it was found that interleukin 5 (IL-5, formerly known as T cell replacing factor/B cell growth factor II) is essential for these polyclonal responses by inhibition of such responses with monoclonal anti-IL-5 antibody. Anti-IL-5 also inhibits specific antibody responses involving direct T:B interaction. Thus, IL-5 is clearly a critical mediator of differentiation to immunoglobulin secretion of activated B cells, whether such B cells are obtained as large B cells from freshly isolated spleen cells or are initially activated in an IL-4-dependent fashion by cognate interaction by a helper T cell clone.     

Human T and B cell immunoreactivity to a recombinant 23-kDa Cryptosporidium parvum antigen.

Cryptosporidial infection in humans results in parasite-specific IgG, IgM, and IgA antibody responses, but little is known of the cell-mediated immune responses to cryptosporidial antigens. In a convenience sample of 35 Haitian residents, there was a high level of cryptosporidial exposure (>90%) as determined by immunoblot reactivity of serum against cryptosporidial antigens. An attempt was made to determine if there was a relationship between antibody and T cell-mediated responses to recombinant Cp23 antigen and how this correlated with reactivity to crude sporozoite antigen preparations (SAg). T cell reactivity was greater against SAg (57%) than to Cp23 (34.3%) as measured by [3H]thymidine incorporation. Proliferative responses to Cp23 were significantly correlated with SAg responses. By enzyme-linked immunosorbent assay, most persons had IgG responses to both SAg (91.4%) and to recombinant Cp23 (88.5%). Antibody responses were greater among persons who exhibited T cell responses to SAg and Cp23. This study demonstrates that recombinant Cp23 antigen could be a useful antigen for detection of both antibody and cell-mediated responses in epidemiologic studies.     

Regulation of innate immune responses by nucleic acid analogues

The activation of innate immune responses by nucleic acids is critical to host responses against pathogens, such as viruses; however, nucleic acids can also trigger the development and/or exacerbation of pathogenic responses such as autoimmunity. We previously demonstrated that the selective activation of nucleic acid-sensing cytosolic and Toll-like receptors is contingent on the promiscuous sensing of nucleic acids by high-mobility group box proteins (HMGBs). Basides these findings, we also found that nonimmunogenic nucleotide with high-affinity HMGB binding, termed ISM ODN, functions as suppressing agent for nucleic acid-activated innate immune responses. In this review, we aim to summerize this novel feature of HMGB proteins in nucleic acid-mediated innate immune responses. In addition, we will discuss the inhibitory effect of nonimmunogenic oligodeoxynucleotides (ni-ODNs) targeting HMGB proteins.     

Spike-directed vaccination elicits robust spike-specific T-cell response,including to mutant strains

Although most studies describing coronavirus disease 2019 vaccine responses have focused on antibodies, there is increasing evidence that T cells play a critical role. Here the authors evaluated T-cell responses in seronegative donors before and after vaccination to define responses to the severe acute respiratory syndrome coronavirus 2 reference strain as well as to mutations in the variant strains Alpha/B.1.1.7 and Beta/B.1.351. The authors observed enhanced T-cell responses to reference and variant spike strains post-vaccination.     

Paradoxical roles of IFN-gamma in models of Th1-mediated autoimmunity

T-cell responses to antigens are classified on the basis of the cytokines they produce as either Th1 (IFN-gamma, IL-2) or Th2 (IL-4, IL-10), with these Th types being indicative of either cell-mediated or antibody-mediated responses, respectively. Using this classification, T-cell responses in MHC-class-II-restricted autoimmune diseases appear to be predominantly of the Th1 type, based on the presence of high levels of IFN-gamma. This simplistic classification has recently been challenged, however, as disease incidence and severity are frequently elevated in animals that have a deficient IFN-gamma response. The recent data discussed here indicate that the cytokine circuits involved in the regulation of cell-mediated and humoral immune responses during the development of autoimmune arthritis are more complex than originally proposed; perhaps our characterization of autoimmune responses as strictly Th1 or Th2 is overly simplistic, especially as it pertains to the role of IFN-gamma.     

Mucosal administration of CpG oligodeoxynucleotide elicits strong CC and CXC chemokine responses in the vagina and serves as a potent Th1-tilting adjuvant for recombinant gD2 protein vaccination against genital herpes

Although sexually transmitted pathogens are capable of inducing pathogen-specific immune responses, vaginal administration of nonreplicating antigens elicits only weak, nondisseminating immune responses. The present study was undertaken to examine the potential of CpG-containing oligodeoxynucleotide (CpG ODN) for induction of chemokine responses in the genital tract mucosa and also as a vaginal adjuvant in combination with glycoprotein D of herpes simplex virus type 2 (HSV-2) for induction of antigen-specific immune responses. We found that a single intravaginal administration of CpG ODN in mice stimulates a rapid and potent response of CC chemokines macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES as well as of CXC chemokines MIP-2 and IP-10 in the vagina and/or the genital lymph nodes. Importantly, intravaginal vaccination with recombinant gD2 in combination with CpG ODN gave rise to a strong antigen-specific Th1-like immune response in the genital lymph nodes as well as the spleens of the vaccinated mice. Further, such an immunization scheme conferred both systemic and mucosal immunoglobulin G antibody responses as well as protection against an otherwise lethal vaginal challenge with HSV-2. These results illustrate the potential of CpG ODN for induction of potent chemokine responses in the genital tract and also as a vaginal adjuvant for generation of Th1-type mucosal and systemic immune responses towards a nonreplicating antigen derived from a sexually transmitted pathogen. These data have implications for the development of a mucosal vaccine against genital herpes and possibly other sexually transmitted diseases.