T-cell inhibition of humoral responsiveness. II. Theory on the role of restrictive recognition in immune regulation.

A general theory is presented which deals with the finding that effector T-cell inhibitory and cytotoxic activity are K/D-restricted whereas effector T-cell cooperating activity and delayed-hypersensitivity are I-restricted. It is argued that this fact alone requires the T-cell receptor to be dual-recognative. Within the framework of the associative recognition (“two-signal”) theory, a dual-recognition model of restrictive recognition is proposed. The questions dealt with derive from our previous study (1): (1) Under what conditions may effector T-cell function be unrestricted? (2) Are paralysis and induction of antigen-sensitive t-cells restricted? (3) What determines restrictive specificity and the relationship between restriction and T-cell function? (4) What are the expected characteristics of the germ-line genes which encode the T-cell receptor?The elements of the minimal model are: (1) The T-cell expresses a receptor consisting of an anti-self MHC (S) site and an anti-antigen (X) site physically linked to each other and to a signal donor site. (2) The target cell has on its surface the antigenic determinant, X, and the restricting element, S(K/D or I), linked to a signal acceptor site. (3) Restricted signaling requires (a) an interaction between X and anti-X and (b) the positioning of the acceptor with respect to the donor, i.e. formation of a “synapse,” by an interaction between S and anti-S. (4) The acceptor linked to K/D can read inhibitory and cytotoxic signals whereas the acceptor linked to I can read cooperative and delayed-hypersensitivity signals. (5) The paralysis and induction of antigen-sensitive t-cells can be unrestricted (the anti-S site of the t-cell need not be occupied). All signals to the t-cell are initiated uniquely by the X-anti-X interaction. (6) Positive selection in the thymus via an S anti-S interaction between a pre-t-cell expressing anti-S with a “restricting cell,” expressing S, fixes the specificity of restrictive recognition as well as the appropriate effector function. (7) Proposition: The t-cell receptor is H-2 encoded.The data presented earlier (1, 14) as well as the competing Janeway-Binz-Wigzell dual-recognition model (59) are analyzed.     

High frequency and nonrandom distribution of alloreactivity in T cell clones selected for recognition of foreign antigen in association with self class II molecules

Previous studies have demonstrated that a single T cell clone can respond to both a foreign antigen in the context of self major histocompatibility complex (MHC)-encoded molecules (self plus X) and to an allogeneic class I or class II molecule in the absence of antigen (non-self). We have used limiting dilution of T cells obtained from the draining lymph nodes of antigen-primed B10.A mice to establish a large number of T cell clones that recognize either GAT, pigeon cytochrome c, or sheep insulin in association with syngeneic antigen-presenting cells. Sixty-two antigen-specific T cell clones were assayed for their ability to proliferate in response to a panel of nine different allogeneic haplotypes. Of these, 38 (61%) responded to at least one allogeneic haplotype, and 15 of the 38 (39%) responded to more than one allogeneic stimulator. In addition, the patterns of alloreactivity varied with the immunizing antigen. The GAT-specific T cells had at least one responder to every haplotype tested, although H-2u-responsive T cell clones were the most common. In contrast, no pigeon cytochrome c-specific T cells responded to stimulators of the H-2u haplotype, but rather predominantly responded to H-2t4/H-2s and H-2i5/H-2b. Finally, sheep insulin-reactive T cell clones preferentially responded to H-2u stimulators, although stimulation by antigen-presenting cells of the H-2p and H-2q haplotypes was also common. A chi 2 analysis of the data demonstrated that the dependence of the pattern of alloreactivity observed upon the antigen used for immunization was statistically significant (p less than 0.01). The high frequency of alloreactivity found in antigen-specific T cell clones is discussed, as well as the implications that the antigen-dependent skewing of the distribution of alloreactivity have for a one-receptor model vs a two-receptor model of T cell recognition.     

The molecular basis of alloreactivity in antigen-specific, major histocompatibility complex-restricted T cell clones

We have studied the relationship between major histocompatibility complex (MHC)-restricted antigen recognition and alloreactivity by examining T cell receptor (TCR) alpha and beta gene expression in cytochrome c-specific, Ek alpha:Ek beta (Ek)-restricted helper T cell clones derived from B10.A mice. The clones could be segregated on the basis of four distinct alloreactivity patterns. Clones cross-reactive for three different allogeneic la molecules (As alpha:As beta [As], Ab alpha:Ab beta [Ab], Ek alpha: Eb beta [Eb]) expressed the same V alpha and V beta gene segments, generating the distinct alloreactive specificities via unique V alpha-J alpha and V beta-D beta-J beta joining events. Ek alpha:Es beta (Es)-alloreactive B10.A clones expressed the same V alpha, J alpha, and V beta segments as an Es-restricted, Ek-alloreactive, cytochrome c-specific, H-2-congenic B10.S(9R) clone. This homology between TCRs mediating allorecognition of la molecules and recognition of the same la molecules as restriction elements associated with nominal antigen suggests that MHC-restricted recognition and allorecognition represent differences in the affinity of the TCR-MHC molecule interaction.     

Lung and chest wall impedances in the dog: effects of frequency and tidal volume.

Dependences of the mechanical properties of the respiratory system on frequency (f) and tidal volume (VT) in the normal ranges of breathing are not clear. We measured, simultaneously and in vivo, resistance and elastance of the total respiratory system (Rrs and Ers), lungs (RL and EL), and chest wall (Rcw and Ecw) of five healthy anesthetized paralyzed dogs during sinusoidal volume oscillations at the trachea (50-300 ml, 0.2-2 Hz) delivered at a constant mean lung volume. Each dog showed the same f and VT dependences. The Ers and Ecw increased with increasing f to 1 Hz and decreased with increasing VT up to 200 ml. Although EL increased slightly with increasing f, it was independent of VT. The Rcw decreased from 0.2 to 2 Hz at all VT and decreased with increasing VT. Although the RL decreased from 0.2 to 0.6 Hz and was independent of VT, at higher f RL tended to increase with increasing f and VT (i.e., as peak flow increased). Finally, the f and VT dependences of Rrs were similar to those of Rcw below 0.6 Hz but mirrored RL at higher f. These data capture the competing influences of airflow nonlinearities vs. tissue nonlinearities on f and VT dependence of the lung, chest wall, and total respiratory system. More specifically, we conclude that 1) VT dependences in Ers and Rrs below 0.6 Hz are due to nonlinearities in chest wall properties, 2) above 0.6 Hz, the flow dependence of airways resistance dominates RL and Rrs, and 3) lung tissue behavior is linear in the normal range of breathing.     

Insulin-specific human T cells. Epitope specificity, major histocompatibility complex restriction, and alloreactivity to a diabetes-associated haplotype

T cells from an insulin-treated diabetic (ML, HLA DR1, w6) were stimulated in vitro with insulin, cloned at limiting dilution, and examined for their fine specificity and genetic restriction. T cell lines (TCL) derived from beef insulin stimulation were highly specific for epitopes on beef insulin, whereas pork insulin stimulation generated T cells that recognized determinants shared with beef insulin. Included among TCL reactive with pork insulin is one line (P2/9) that is autoreactive with human insulin. Antigen-presenting cells of known HLA type and monoclonal antibodies directed at class II major histocompatibility complex antigens were used to confirm the role of HLA-DR in restricting the response of insulin immune T cells. No preference or determinant selection within the donor's haplotypes was identified because either DR1 or DRw6 antigen-presenting cells could present the A loop of beef insulin. A TCL that recognized the A loop of beef insulin in association with DR1 was also alloreactive to HLA DR3, or a molecule closely linked to it, in the absence of insulin. A second T cell clone with insulin specificity and alloreactivity was also derived by allo stimulation of the donor's cells with DR3+ cells. When tested with a series of DR3+ stimulator cells, the alloreactivity was directed at diabetes-associated haplotypes. These data show that the T cell repertoire for insulin of a single diabetic donor encompasses that of multiple inbred animal strains and includes fine specificity for one to two amino acids, recognition of autologous insulin, and cross-reactivity with an allogeneic major histocompatibility complex antigen.     

The helper T-cell repertoire of mice expressing class II major histocompatibility complex β chains in the absence of α chains

 Mutant mice generated by disrupting the H2-Aa ^b major histocompatibility complex (Mhc) gene are demonstrated here to express Aβ^b chains in the absence of α chains. These mice possess a CD4⁺ helper T cell (Th) repertoire that uses predominantly the Vβ7 T-cell antigen receptor (Tcr) segment for recognition of any protein antigen presented by the α-free Aβ molecule. As an alloantigen, the Aα-free Aβ molecule is recognized very poorly by T cells from a series of class II disparate mouse strains, indicating that it is grossly different from normal α/β heterodimers. Indeed, molecular modeling suggests a β/β homodimer arrangement with an altered geometry of the Tcr contact area. Interestingly, the mutant mice exhibit normal alloreactivity, without a restricted Vβ usage, toward a series of foreign α/β class II heterodimers, although their T cells developed in the absence of such heterodimers. Thus, the complementarity of Tcr to normal α/β heterodimers, and thereby also alloreactivity, appears to be an ontogeny independent (i. e., germline-encoded) feature. Received: 30 September 1996 / Revised: 18 October 1996     

Effects of sleep-induced increases in upper airway resistance on ventilation

To determine the effects of the sleep-induced increases in upper airway resistance on ventilatory output, we studied five subjects who were habitual snorers but otherwise normal while awake (AW) and during non-rapid-eye-movement (NREM) sleep under the following conditions: 1) stage 2, low-resistance sleep (LRS); 2) stage 3-4, high-resistance sleep (HRS) (snoring); 3) with continuous positive airway pressure (CPAP); 4) CPAP + end-tidal CO2 partial pressure (PETCO2) mode isocapnic to LRS; and 5) CPAP + PETCO2 isocapnic to HRS. We measured ventilatory output via pneumotachograph in the nasal mask, PETCO2, esophageal pressure, inspiratory and expiratory resistance (RL,I and RL,E). Changes in PETCO2 were confirmed with PCO2 measurements in arterialized venous blood in all conditions in one subject. During wakefulness, pulmonary resistance (RL) remained constant throughout inspiration, whereas in stage 2 and especially in stage 3-4 NREM sleep, RL rose markedly throughout inspiration. Expired minute ventilation (VE) decreased by 12% in HRS, and PETCO2 increased in LRS (3.3 Torr) and HRS (4.9 Torr). CPAP decreased RL,I to AW levels and increased end-expiratory lung volume 0.25-0.93 liter. Tidal volume (VT) and mean inspiratory flow rate (VT/TI) increased significantly with CPAP. Inspiratory time (TI) shortened, and PETCO2 decreased 3.6 Torr but remained 1.3 Torr above AW. During CPAP (RL,I equal to AW), with PETCO2 returned to the level of LRS, VT/TI and VE were 83 and 52% higher than during LRS alone. Also on CPAP, with PETCO2 made equal to HRS, VT, VT/TI, and VE were 67, 112, and 67% higher than during HRS alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung and chest wall impedances in the dog in normal range of breathing: effects of pulmonary edema.

We evaluated the effect of pulmonary edema on the frequency (f) and tidal volume (VT) dependences of respiratory system mechanical properties in the normal ranges of breathing. We measured resistance and elastance of the lungs (RL and EL) and chest wall of four anesthetized-paralyzed dogs during sinusoidal volume oscillations at the trachea (50-300 ml, 0.2-2 Hz), delivered at a constant mean airway pressure. Measurements were made before and after severe pulmonary edema was produced by injection of 0.06 ml/kg oleic acid into the right atrium. Chest wall properties were not changed by the injection. Before oleic acid, EL increased slightly with increasing f in each dog but was independent of VT. RL decreased slightly and was independent of VT from 0.2 to 0.4 Hz, but above 0.4 Hz it tended to increase with increasing flow, presumably due to the airway contribution. After oleic acid injection, EL and RL increased greatly. Large negative dependences of EL on VT and of RL on f were also evident, so that EL and RL after oleic acid changed two- and fivefold, respectively, within the ranges of f and VT studied. We conclude that severe pulmonary edema changes lung properties so as to make behavior VT dependent (i.e., nonlinear) and very frequency dependent in the normal range of breathing.     

A Multifunctional Region of the Shigella Type 3 Effector IpgB1 Is Important for Secretion from Bacteria and Membrane Targeting in Eukaryotic Cells

Type 3 secretion systems are complex nanomachines used by many Gram–negative bacteria to deliver tens of proteins (effectors) directly into host cells. Once delivered into host cells, effectors often target to specific cellular loci where they usurp host cell processes to their advantage. Here, using the yeast model system, we identify the membrane localization domain (MLD) of IpgB1, a stretch of 20 amino acids enriched for hydrophobic residues essential for the targeting of this effector to the plasma membrane. Embedded within these residues are ten that define the IpgB1 chaperone-binding domain for Spa15. As observed with dedicated class IA chaperones that mask hydrophobic MLDs, Spa15, a class IB chaperone, promotes IpgB1 stability by binding this hydrophobic region. However, despite being stable, an IpgB1 allele that lacks the MLD is not recognized as a secreted substrate. Similarly, deletion of the chaperone binding domains of IpgB1 and three additional Spa15-dependent effectors result in alleles that are no longer recognized as secreted substrates despite the presence of intact N-terminal secretion signal sequences. This is in contrast with MLD-containing effectors that bind class IA dedicated chaperones, as deletion of the MLD of these effectors alleviates the chaperone requirement for secretion. These observations indicate that at least for substrates of class IB chaperones, the chaperone-effector complex plays a major role in defining type 3 secreted proteins and highlight how a single region of an effector can play important roles both within prokaryotic and eukaryotic cells.     

Nonlinearity and harmonic distortion of dog lungs measured by low-frequency forced oscillations

The nonlinearity of lung tissues and airways was studied in six anesthetized and paralyzed open-chest dogs by means of 0.1-Hz sinusoidal volume forcing at mean transpulmonary pressures (Ptp) of 5 and 10 cmH2O. Lung resistance (RL) and elastance (EL) were determined in a 32-fold range (15-460 ml) of tidal volume (VT), both by means of spectrum analysis at the fundamental frequency and with conventional time-domain techniques. Alveolar capsules were used to separate the tissue and airway properties. A very small amplitude dependence was found: with increasing VT, the frequency-domain estimates of RL decreased by 5.3 and 14%, whereas EL decreased by 20 and 22% at Ptp = 5 and 10 cmH2O, respectively. The VT dependences of the time-domain estimates of RL were higher: 10.5 and 20% at Ptp = 5 and 10 cmH2O, respectively, whereas EL remained the same. The airway resistance increased moderately with flow amplitude and was smaller at the higher Ptp level. Analysis of the harmonic distortions of airway opening pressure and the alveolar pressures indicated that nonlinear harmonic production is moderate even at the highest VT and that VT dependence is homogeneous throughout the tissues. In three other dogs it was demonstrated that VT dependences of RL and EL were similar in situ and in isolated lungs at both Ptp levels.     

Quantifying the coevolutionary potential of multistep immune defenses

Coevolutionary models often assume host infection by parasites depends on a single bout of molecular recognition. As detailed immunological studies accumulate, however, it becomes increasingly apparent that the outcome of host–parasite interactions more generally depends on complex multiple step infection processes. For example, in plant and animal innate immunity, recognition steps are followed by downstream effector steps that kill recognized parasites, with the outcome depending on an escalatory molecular arms race. Here, we explore the consequences of such multistep infection processes for coevolution using a genetically explicit model. Model analyses reveal that polymorphism is much greater at recognition loci than effector loci, that host–genotype by parasite–genotype (G_h × G_p) interactions are larger for the recognition step, and that the recognition step contributes more to local adaptation than the effector step. These results suggest that (1) local adaptation is more likely when fitness measures are related to recognition versus downstream effectors, (2) effector loci, while mechanistically important, are less likely to harbor the G_h × G_p variation that fuels coevolution, and (3) recognition loci are better candidates for genomic hotspots of coevolution.     

Host Protein BSL1 Associates with Phytophthora infestans RXLR Effector AVR2 and the Solanum demissum Immune Receptor R2 to Mediate Disease Resistance

Plant pathogens secrete effector proteins to modulate plant immunity and promote host colonization. Plant nucleotide binding leucine-rich repeat (NB-LRR) immunoreceptors recognize specific pathogen effectors directly or indirectly. Little is known about how NB-LRR proteins recognize effectors of filamentous plant pathogens, such as Phytophthora infestans. AVR2 belongs to a family of 13 sequence-divergent P. infestans RXLR effectors that are differentially recognized by members of the R2 NB-LRR family in Solanum demissum. We report that the putative plant phosphatase BSU-LIKE PROTEIN1 (BSL1) is required for R2-mediated perception of AVR2 and resistance to P. infestans. AVR2 associates with BSL1 and mediates the interaction of BSL1 with R2 in planta, possibly through the formation of a ternary complex. Strains of P. infestans that are virulent on R2 potatoes express an unrecognized form, Avr2-like (referred to as A2l). A2L can still interact with BSL1 but does not promote the association of BSL1 with R2. Our findings show that recognition of the P. infestans AVR2 effector by the NB-LRR protein R2 requires the putative phosphatase BSL1. This reveals that, similar to effectors of phytopathogenic bacteria, recognition of filamentous pathogen effectors can be mediated via a host protein that interacts with both the effector and the NB-LRR immunoreceptor.     

Alteration of the metastatic potential of line 1 lung carcinoma cells: opposite effects of class I antigen induction by interferons versus DMSO or gene transfection.

Class I antigens are necessary for the recognition of tumor cells by cytotoxic T lymphocytes (CTL). The line 1 lung carcinoma is a spontaneous murine tumor deficient in class I antigen expression. Consistent with this, line 1 cells are highly metastatic in vivo. We investigated whether increasing class I antigen expression on line 1 cells could alter the metastatic potential of these tumor cells using an in vivo lung metastasis model. We used three methods to induce class I antigen expression on line 1 cells: gene transfection, treatment with dimethyl sulfoxide (DMSO), or treatment with interferon (IFN)-beta or -gamma. We found that line 1 cells expressing a transfected class I gene were significantly less metastatic than parental line 1 cells. DMSO-treated line 1 cells also formed significantly fewer metastases than parental line 1 cells. These results indicate that increased class I antigen expression decreases the metastatic potential of line 1 cells in vivo. However, we did not observe a significant decrease in the number of lung metastases in mice receiving line 1 cells treated with IFN-beta or -gamma, despite high levels of class I antigen expression. Thus, increasing class I antigen expression with IFN has an opposite effect on metastasis from class I antigen expression induced by transfection or DMSO. These results show that the method used to increase class I antigen expression is critical in terms of the in vivo effect observed. To investigate a possible mechanism for the differences observed in vivo between these class I expressing cells, we tested whether IFN alters or blocks susceptibility of line 1 cells to immune effector cells. We found IFN treatment increased the ability of line 1 cells to be recognized by CTL but concomitantly decreased the susceptibility of line 1 cells to NK cell lysis by a non-class I antigen-related mechanism. In contrast, transfected or DMSO-treated line 1 cells which were less metastatic in vivo were susceptible to both CTL and NK-mediated lysis. Taken together, these results suggest that immune intervention against metastasizing line 1 cells may involve NK cells and CTL.     

Evolution of the translation termination factors

During of protein synthesis, or translation, four stages are usually recognized: initiation, elongation, termination, and recycling. Translation termination involves two protein types, the factors of termination of the first class participate in recognition of stop-codons and the termination factors of the second class are GTP-ases, which stimulate activity of the first class factors. Bacteria have two proteins of class 1, RF1 and RF2 (release factor), with overlapping codon specificity; both factors are capable to recognize the codon UAA, while the codons UAG and UGA are only decoded by RF1 and RF2, respectively. In addition, bacteria contain one factor of class 2, RF3, which not only stimulates activity of RF1 and RF2, but also promotes release of the first class factors after completion of termination. In contrast to prokaryotes, eukaryotic organisms have only one termination factor of class 1, eRF1. This protein recognizes each of the three stop-codons, which results in hydrolysis of peptidyl-tRNA. Eukaryotic cells also have only one factor of class 2, eRF3.     

Simulated Interactions between a Class III Antiarrhythmic Drug and a Figure 8 Reentry

Ventricular Fibrillation is responsible for a majority of sudden cardiac death, but little is known about how ventricular tachycardia (VT) degenerates into ventricular fibrillation. Several clinical studies focused only on preventing VT with a class III antiarrhythmic drug resulted in many deaths. Our simulations investigate the interactions between an antiarrhythmic drug likely to suppress a VT and a Figure 8 reentry. A parameter AAR is introduced to increase the action potential duration and therefore simulate various Class III drugs. Simulations are ran under several conditions (phases of the reentry, values of AAR, durations). They show that a VT can be suppressed whatever the phase of the reentry but it strongly depends on the duration of the effect. It confirms that a drug which can suppress a reentry can also worsen it. It also shows a great variety of activation patterns and thus the complexity of antiarrhythmic drugs effects. Simulations also demonstrate that suppressing VT is an increasing function of AAR.     

Easy assessment of ES cell clone potency for chimeric development and germ-line competency by an optimized aggregation method.

Production of germ-line competent chimeric mice from embryonic stem (ES) cells is an inevitable step in establishing gene-manipulated mouse lineages. A common method used for creating chimeric mice is the injection of ES cells into the blastocoelic cavity (blastocyst injection). The aggregation method is an alternative way to introduce ES cells to the host embryo which is less difficult than blastocyst injection. Here we re-examined the condition of embryo-ES cell coculture on the aggregation method and found improvement of germ-line competent chimeric production by a simple modification of the coculture medium. Moreover, R1 ES cell and its 10 gene-manipulated subclones were tested by this method. Although all ES cell clones showed good morphology and a normal karyotype, the efficiency of chimeric development and germ-line transmission varied among clones and were classified into three grades according to germ-line competency. In the first group (class A), both the incidence of chimera with high ES cell contribution and the rate of germ-line transmission were fairly high. Germ-line competent chimeras were obtained but with rather low efficiency in the second group (class B), while another group (class C) showed an absence of high ES cell-contributed chimeras and no germ-line transmission. These results suggest the usefulness of this modified aggregation method to predict the potency of ES cell clones for germ-line competency.     

Mechanical impedance as determinant of inspiratory neural drive during exercise in humans

Five healthy males exercised progressively with small 2-min increments in work load. We measured inspiratory drive (occlusion pressure, P0.1), pulmonary resistance (RL), dynamic pulmonary compliance (Cdyn), transdiaphragmatic pressure (Pdi), and diaphragmatic electromyogram (EMGdi). Minute ventilation (VE), mean inspiratory flow rate (VT/TI), and P0.1 all increased exponentially with increased work load, but P0.1 increased at a faster rate than did VT/TI or VE. Thus effective impedance (P0.1/VT/TI) rose throughout exercise. The increasing P0.1 was mostly due to augmented Pdi and coincided with increased EMGdi during this initial portion of inspiration. We found no consistent change in RL or Cdyn throughout exercise. With He breathing (80% He-20% O2), RL was reduced at all work loads; P0.1 fell in comparison with air-breathing values and VE, VT, and VT/TI rose in moderate and heavy work; and P0.1/VT/TI was unchanged with increasing exercise loads. Step reductions in gas density at a constant work load of any intensity showed an immediate reduction in the rate of rise of EMGdi and Pdi followed by increased VT/TI, breathing frequency, and hypocapnia. These changes were maintained during prolonged periods of unloading and were immediately reversible on return to air breathing. These data are consistent with the existence of a reflex effect on the magnitude of inspiratory neural drive during exercise that is sensitive to the load presented by the normal mechanical time constant of the respiratory system. This "load" is a significant determinant of the hyperpneic response and thus of the maintenance of normocapnia during exercise.     

T lymphocyte-dependent B lymphocyte proliferative response to antigen. II. Induction of polyclonal B lymphocyte activation of normal B cells and of Lyb-5- B cells from xid mice via recognition of self-IA antigens

We extended our investigations into the genetic requirements and antigen dependence for the induction of polyclonal B lymphocyte proliferation by primed T lymphocytes. By using recombinant inbred mouse strains and antigen-specific T lymphocyte clones that lack alloreactivity, the genetic requirement was mapped to the IA subregion of the MHC. Furthermore, approaches that prevented or limited the accessibility of antigens to the B lymphocyte surface demonstrated that antigen binding onto the B lymphocyte surface was probably not necessary for induction of B lymphocyte proliferation. These experiments suggest strongly that T lymphocyte recognition of B lymphocyte Ia molecules in the absence of sIg cross-linking or in the absence of antigen bound nonspecifically to B lymphocytes can cause cellular activation. Similar T lymphocyte-dependent B lymphocyte activation was seen when Lyb-5- cells from CBA/N mice with the xid defect were cultured. Increases in the number of cells secreting immunoglobulins could be detected in the proliferating B lymphocyte cultures, suggesting that the culture conditions had fulfilled the requirements for B lymphocyte differentiation into antibody-producing cells. Although anti-Ig did not interfere with the B lymphocyte proliferative responses, it did diminish the number of cells secreting immunoglobulins. The implications of these experiments in extending our understanding of the activation pathway of Lyb-5- and Lyb-5+ B lymphocytes are discussed.     

MAMPs and MIMPs: proposed classifications for inducers of innate immunity

Plants encode a sophisticated innate immune system. Resistance against potential pathogens often relies on active responses. Prerequisite to the induction of defences is recognition of the pathogenic threat. Significant advances have been made in our understanding of the non-self molecules that are recognized by plants and the means by which plants perceive them. Established terms describing these recognition events, including microbe-associated molecular pattern (MAMP), MAMP-receptor, effector, and resistance (R) protein, need clarification to represent our current knowledge adequately. In this review we propose criteria to classify inducers of plant defence as either MAMPs or microbe-induced molecular patterns (MIMPs). We refine the definition of MAMP to mean a molecular sequence or structure in ANY pathogen-derived molecule that is perceived via direct interaction with a host defence receptor. MIMPs are modifications of host-derived molecules that are induced by an intrinsic activity of a pathogen-derived effector and are perceived by a host defence receptor. MAMP-receptors have previously been classified separately from R-proteins as a discrete class of surveillance molecules. However, MAMP-receptors and R-proteins cannot be distinguished on the basis of their protein structures or their induced responses. We propose that MAMP-receptors and MIMP-receptors are each a subset of R-proteins. Although our review is based on examples from plant pathogens and plants, the principles discussed might prove applicable to other organisms.     

Immune response to acute virus infection in the Syrian hamster

Syrian hamsters show evidence of classical T-cell-mediated immune reactivity to acute virus infection as judged by primary foot pad swelling, kinetics of in vitro cytotoxic activity, and virus specificity of cytotoxic effector cells. In spite of this, no evidence of genetic restriction is observed among the variety of allodisparate inbred strains tested. This virus-induced, cell-mediated killing extends across strain barriers despite strong cellular and serologic alloreactivity among some of the strains utilized. To account for the apparent lack of genetic restriction, we currently favor the hypothesis that all hamsters examined thus far share at least one class I MHC antigen. Since these animals differ at hamster loci which elicit MLR, GVHR, acute SGR, CML, and alloantibody, we presume class II MHC polymorphism exists in this species. The presence of putative class II MHC polymorphism without detectable class I MHC polymorphism is unusual among mammals examined to date, and of unknown biologic significance.