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In this paper, we proposed a multidelayed in‐host HIV model to represent the interaction between human immunodeficiency virus and immune response. One delay was considered to incorporate the time required by the virus for various intracellular events to make a host cell productively infective, and the second delay was introduced to take into account the time required for adaptive immune system to respond against infection. We extensively analyzed this multidelayed model analytically and numerically. We show that delay may have both destabilizing and stabilizing effects even when the system contains a single immune response delay. It happens when there exists two sequences of critical values of this delay. If the system starts with stable state in absence of delay, then the smallest value of these critical delays causes instability and the next higher value causes stability. The system may also show stability switching for different values of the virus replication factor. These results demonstrate the possible reasons of intrapatients and interpatients variability of CD4+ T cells and virus counts in HIV‐infected patients. [ABSTRACT FROM AUTHOR]

Decisions by uncommitted cells to differentiate down one lineage pathway or another is fundamental to developmental biology. In the immune system, lymphocyte precursors commit to T- or B-cell lineages and T-cell precursors to CD4 or CD8 independently of foreign antigen. T and B cells must also decide whether or not to respond to antigen and when a response is initiated, what sort of response to make such as the type of antibody, CD4 or CD8, and CD4 Th1 or Th2. The two basic mechanisms for these decision-making processes are selection and instruction. Selection depends on prior stochastic production of precommitted cells, which are then selected to respond by an appropriate signal; for example, CD8 and CD4 responses selected by peptide presented in association with major histocompatibility complex class I or II. In contrast, instruction occurs when an uncommitted precursor embarks upon a differentiation pathway in response to a particular set of signals; for example, Th1 and Th2 lineage commitment. In this paper, the signals that determine Th1 and Th2 differentiation are examined with a mathematical model and shown to act as a bistable switch permitting either Tbet or Gata3 to be expressed in an individual cell but not both. The model is used to show how the Tbet Gata3 network within an individual cell interacts with cytokine signals between cells and suggests how Th1 and Th2 lineage commitment can become irreversible. These considerations provide an example of how mathematical models can be used to gain a better understanding of lymphocyte differentiation in an immune response.Immunology and Cell Biology (2007) 85, 300–305; doi:10.1038/sj.icb.7100060; published online 1 May 2007 [ABSTRACT FROM AUTHOR]

Obesity is becoming one of the most serious public health problems in industrialized societies, due to the profound changes in lifestyle, and notably in nutrition. Beside diabetes, cardiovascular diseases or hypertension, increased susceptibility to infection is one of the pathological consequences of being overweight. In this paper, we have assessed the influence of a high-fat diet (HFD) rich in saturated fatty acids on the immune system of DO11.10 mice, which are transgenic for a T-cell receptor specifically recognizing a peptide of ovalbumin. We showed that the specific T-cell immune response was impaired by high-fat feeding, and that the expression of this defect is different depending on whether T cells are naive or Ag experienced. Indeed, on in vitro ovalbumin stimulation, spleen T cells from naive HFD-fed transgenic mice showed proliferation similar to that of cells from standard diet (SD)-fed mice, but exhibited a strong inflammatory profile as shown by the markedly increased IFN- γ/IL-4 ratio. Inversely, spleen T cells from ovalbumin-immunized HFD mice were impaired in their Ag-dependent proliferation compared to cells from SD mice. By co-culture experiments, we showed that both T cells and antigen-presenting cells were involved in this impairment. Moreover, in ovalbumin-immunized HFD animals, a trend towards Th2 response was noted, compared to immunized SD mice. This data implies that naive T cells could participate actively in the low-grade systemic inflammation observed in overweight patients. Moreover, the impaired activity of Ag-experienced T cells could have major consequences both in defence against infection and/or in vaccination protocols. [ABSTRACT FROM AUTHOR]

The in vitro polyclonal pokeweed mitogen (PWM)-induced activation of human B lymphocytes is enhanced by addition of autologous or allogeneic irradiated T cells. This model for B/T-cell cooperation may be used to define and describe the balance between T helper and T suppressor phenomena. The present study investigates the helper and suppressor capacities of mononuclear cells isolated from peripheral blood of infectious mononucleosis patients during the acute disease and the reconvalescence period. During the acute disease we found a functional lack of T helper capacity; furthermore, the T cells were able to suppress the PWM and T-cell-dependent B-cell proliferation of healthy donor cells. The suppression was non-cytotoxic; i.e. not due to destruction of the responder cells. This phenomenon of non-cytotoxic suppression was found for all seven patients studied and disappeared during the reconvalescence period, indicating that the T lymphocytosis seen in infectious mononucleosis includes an expansion of T suppressor cells. [ABSTRACT FROM AUTHOR]

Bone marrow cells and thymus cells were observed in cell transfer expehments to collaborate in the production of anti-BSA antibodies. The target cells for tolerance induction either with a 'low dose' of antigen (100 µg of deaggregated BSA once a week × 5) or with a 'high dose' (a single injection of 5000 µg) were identified by the same technique. In 'low dose' tolerance, some indication was obtained that thymus-derived cells in peripheral lymphoid systems were the target cells; bone marrow-derived cells appeared not to be so susceptible, and the cells residing in thymus or bone marrow seemed to remain unimpaired, in contrast, the injection of a 'high dose' of tolerogen rendered both types of cells in spleen, thymus cells and bone marrow cells, unresponsive or hyporesponsive in parallel with one another. [ABSTRACT FROM AUTHOR]

Immune responses during infection, injury, and cancer proceed in the presence of tissue injury and cell death. Consequently, the system must deal with its own dead cells while it determines the appropriate response to the invader. As apoptotic cells are known to induce immune tolerance and necrotic cells can be potent stimulators of immunity, this decision becomes more complex. The key to understanding the immunologic choices made during cell death is to examine the mechanisms of tolerance induction by dying cells and then relate them to the mechanisms of immunity. Ideally, immunogenic cell death should be directed toward tumor cells and infected cells, whereas tolerogenic cell death should be associated with preventing unwanted immune responses to self. In this review, we discuss how the decision is made by focusing on the biochemical process of cell death and how its key components can influence both tolerance and immunity. [ABSTRACT FROM AUTHOR]

In broadening the integrity model, Zlatko Dembic provided one of the few plausible explanations for the existence of regulatory T cells that has been postulated to date and at the same time highlighted deficiencies of the associative antigen recognition model. In defending the virtues of associative antigen recognition, Melvin Cohn has challenged the integrity model and the concept that regulatory T cells have a role in defining the specificity of immune responses. The critique of Cohn’s analysis I present here suggests that a greater consideration of quantitative evolutionary constraints removes most of the challenges to integrity. [ABSTRACT FROM AUTHOR]

The immune system defends the host against pathogenic attacks by micro-organisms and their products. It does not react against self-components due to the relatively efficient negative selection of developing T lymphocytes in the thymus. This process does permit T cells with low avidity against self to be present in the T cell repertoire. Such cells play an important physiological role as the host needs so-called autoimmune reactions in order to eliminate dying cells or transformed tumour cells. One of the mysteries in immunology is how the host maintains beneficial autoimmune reactions and avoids pathogenic autoimmune reactions. Activation of the adaptive T lymphocytes is mediated by the low avidity interaction between T-cell antigen receptors and antigenic peptides associated with major histocompatibility complex class I or class II molecules. This interaction is strengthened by T-cell co-receptors such as CD2, CD4, CD8, CD28 and CD154, which react with ligands expressed by cells of the innate immune system. In recent years, the importance of pre-activation of the innate immune system for initiation of adaptive T-cell immune responses has been appreciated. In the present review, I will summarize our work on how natural immunity plays an important role in determining the level of beneficial autoimmune reactions against cancer. [ABSTRACT FROM AUTHOR]

The concept of T-cell dependent regulation of immune responses has been a central tenet of immunological thinking since the delineation of the two cell system in the 1960s. Indeed T-cell dependent suppression was discovered before MHC restriction. When reviewing the data from the original wave of suppression, it is intriguing to reflect not just on the decline and fall of suppressor T cells in the 1980s, but on their equally dramatic return to respectability over the past decade. Hopefully their resurgence will be supported by solid mechanistic data that will underpin their central place in our current and future understanding of the immune system. [ABSTRACT FROM AUTHOR]

The effects of donor T cells, or their CD8+ subset, on engraftment and tolerance induction in fetal transplantation were evaluated using an F1-into-parent mouse-model that does not permit a graft- versus-host effect. Gestational day 13 C57BL/6 (H-2Kb) fetuses were transplanted with B6D2F1 (H-2Kb/d) light density bone marrow cells (LDBMC) containing 1–2% T cells, T-cell depleted bone marrow cells (TDBMC, <0·1% T cells), or TDBMC with enriched CD8+ T cells (CD8). Chimaerism levels in the peripheral blood, spleen and bone marrow were usually below 0·2% in all groups, indicating that T cells do not improve engraftment without a graft- versus-host effect. A significant, but transient, wave of donor cells was seen in the peripheral blood at 1 month of age in the CD8 and LDBMC groups. Relatively high levels of chimaerism (<17%) were sometimes detected in the peritoneal cavities of recipients. T-cell tolerance specific to donor cells was evaluated in mixed lymphocyte cultures. The CD8 and LDBMC groups had significantly lower T-cell responses than untransplanted controls. These findings indicate that in utero transplantation of haploidentical donor CD8+ or CD3+ cells can help to lessen the immune response of host T cells towards donor cells. The persistence of donor cells in the peritoneal cavity also correlated with tolerance induction. [ABSTRACT FROM AUTHOR]

Human T cells exposed to high concentrations of influenza A virus cause specific suppression of the in vitro antibody response to the virus, but the phenomenon does not require viable T cells. In order lo investigate the mechanism of this form of suppression, IL-2-dependent T cell clones of helper phenotype {CD4 * , HLA-DR' , 1L-2R -) were prepared with specificity for influenza A (Mem/Bel) and B (B HK) viruses and the non-crossreacting antigen purified protein derivative (PPD). When pulsed with high dose MemBel virus, all three clones transferred suppression equally well to effector cultures of syngeneic or allogeneic E ' and E" cells stimulated with an immunogenic dose of the same virus. Thus, although suppression was specific at the level of expression, the induction phase was non-specific and non-major histocompatibitity complex (MHC) restricted and did not involve interaction of antigen with the T cell receptor. HLA-DR. CD3 and CDS determinants were excluded as the binding site for the virus by two colour immunofluorescent staining and flow cytometric analysis. The concentrations of antigen required for high dose suppression inhibited antigen-specific proliferation by the clones; on the other hand, they remained partially sensitive to lL-2 and could still release gamma-interferon. These findings suggest that this phenomenon is distinct from conventional antigen-specific suppression mediated by CD8 T cells, but may play a biologically important role in regulating immune responses at least to viral antigens. [ABSTRACT FROM AUTHOR]

Interferon-γ (IFN-γ) is an important cytokine which regulates inflammatory and immune response mechanisms. IFN-γ enhances the presentation and recognition of antigens by inducing the expression of major histocompatibility complex (MHC) proteins, by activating effector T cells and mononuclear phagocytes, and by modulating immunoglobulin production and class selection in B cells. Inappropriate production of IFN-γ has been implicated in the pathogenesis of several autoimmune and inflammatory diseases and in graft rejection. Here, we describe, a recombinant inhibitor of IFN-γ, termed murine IFN-γ receptor immunoadhesin (mIFN-γR-IgG). We constructed this immunoadhesin by linking the extracellular portion of the mouse IFN-γR to the hinge and Fc region of an IgG1 heavy chain. Murine IFN-γR-IgG is secreted by transfected cells as a disulphide-bonded homodimer which binds IFN-γ bivalently, with high affinity and in a species-specific manner. In vitro, mIFN-γRIgG can block mIFN-γ-induced antiviral activity and expression of the class I MHC antigen H-2Kk in cultured cells. In vivo, mIFN-γ,R-IgG can block the function of endogenous mIFN-γ in mouse models of infection with Listeria monocytogenes and of contact sensitivity. These results show that mIFNγR-IgG is an effective and specific inhibitor of mIFN-γ both in vitro and in vivo. Thus, in general, IFN-γ receptor immunoadhesins may be useful for investigating the biological functions of IFN-γ as well as for preventing deleterious effects of IFN-γ in human disease. [ABSTRACT FROM AUTHOR]

Different concentrations of spleen cells from C57BL.10 mice were activated with lipopolysaccharide (LPS), and DNA synthesis and IgM and IgG secretion were measured. The dilution curve was sigmoid, and the response was rapidly lost below a certain cell concentration. In the presence of thymocytes or spleen cells from the LPS-non-responder strain C57BL.10/ScCr the dilution curve for the LPS response of cells from C57BL.10 mice became linear, and the overall response was increased. Irradiated cells could not restore the response at suboptimal cell concentrations. In addition, enriched T cells restored the response as well as normal spleen cells, whereas enriched B cells did not. We compared the restoring capacity of different filler cells for the LPS response with that of a plasmacytoma cell line cultured at suboptimal cell concentrations. The results are compatible with the idea that the filler cells provide growth-stimulating activity to LPS-responsive cells but growth-supporting activity to the tumour cells. Furthermore, highly enriched B-cell populations respond poorly to LPS, but the response can be partly restored by filler cells. These data suggest that the LPS response is accessory-cell-dependent. [ABSTRACT FROM AUTHOR]

The primary humoral immune response to rat Yoshida ascites sarcoma (YAS) grown in mice was used to study thymus-dependent (T) and bone marrow-derived (B) lymphocyte cooperation. It was shown that B6D2F1 T lymphocytes that do not cooperate with parental B lymphocytes enabled parental B lymphocytes from B6→B6D2F1 radiation chimaeras to reject the tumour. However, when the bone marrow cells from B6→B6D2F1 chimaeras were used to reconstitute parental B6 mice, these B6→B6D2F1→B6 mice lost their tolerance to D2 transplantation antigens, and their B lymphocytes were not able to cooperate with B6D2F1 T lymphocytes. In our search for the reasons for the failure of F, T cells to be effective in parental and P→F1→P TIR mice, rejection of F1 T cells was excluded because; (i) immune reactivity in TIR mice was found to be either absent or minimal: (ii) parental TIR mice did not produce any detectable cytotoxic anti bodies after an intra venous injection of F1 splenic T cells; and (iii) YAS rejection was not induced at very high doses of F1 T cells. However, in a cell transfer system we were able to demonstrate that injection of spleen cells from parental TIR mice could thwart the successful cooperation of transferred F1 T cells with host B cells. Collectively, these data suggest that the changes of the collaborative potential of parental B cells as achieved in the F1 environment could he ascribed to ‘adaptive’ differentiation of B lymphocytes. It appears that the differentiation process that has rendered nonsyngeneic chimaeric cells able to cooperate was independent of the exogenous antigen. [ABSTRACT FROM AUTHOR]

The enhanced stimulation of human B lymphocytes by pokeweed mitogen in the presence of irradiated T helper lymphocytes has been studied, revealing that the proliferative responses measured by incorporation of thymidine in cultures of B lymphocytes and irradiated T lymphocytes in a 1:2 or 1:4 ratio is mostly a function of the B cells. Only a minimal number, if any, of the T cells contaminating the B cell suspensions is stimulated to proliferation. This is in contrast to stimulation of the B-cell suspensions without addition of irradiated T cells, where both B cells and T cells proliferate. The irradiated T helper cells have no FcR for antigen-bound IgG, and as well allogeneic as autologous T cells exhibit helper capacity of equal strength. The test system described makes it possible selectively to test one B-cell function and the corresponding T helper capacity. [ABSTRACT FROM AUTHOR]

Protein-coated silica, a macrophage toxin, was used to assess the requirement for accessory cells in the induction of an in vitro proliferative response to (i) antigens from Actinomyces viscosus and (ii) the mitogens conconavalin A (Con A) and phytohaemagglutinin (PHA). T cells were obtained from RIC-Sprague-Dawley rats primed in vivo with A. viscosus Ny1 by splenectomy and filtering the spleen cell suspensions through Degalan Ig-anti-IgG columns. In the presence of 100 µg silica/ml during 4 days of culture, the proliferative response of T lymphocytes was not diminished. In contrast, when the T cells were precultured with silica for 24 h, washed, and subsequently cultured with the antigen fractions, antigen-induced proliferation was abolished. This procedure, however, had no influence on mitogen-induced T-cell activation. It is therefore concluded that the antigen-dependent anamnestic in vitro response (but not activation by mitogens) of rat T lymphocytes needs help from silica-sensitive macrophages. [ABSTRACT FROM AUTHOR]

Inducibility of immunological tolerance to a T-dependent antigen, human serum albumin, was studied in autoimmune mice (NZB, MRL/Mp-1pr/1pr and male BXSB mice), comparing with non-autoimmune mice (BALB/c, DBA/2, MRL/Mp- +/+ and female BXSB mice). Weekly injections of increasing doses of the tolerogen into DBA/2 mice induced T-cell tolerance without the participation of suppressor cells and without affecting B cells. All of the autoimmune mice tested were refractory to the tolerogen; partial tolerance (40%-60% responsiveness) was attained in mice aged 1 month, but not in older mice. By comparison, tolerance was induced in non-autoimmune mice to a similar degree irrespective of the age of the mice. The tolerance inducibility was also examined in reciprocal bone marrow cell (BMC) transfer experiments between NZB and DBA/2 mice and also BMC transfer into B10.D2 mice. It was shown that recipients of NZB BMC were more resistant to tolerance induction than those of DBA/2 BMC, while irradiated NZB mice receiving DBA/2 BMC were susceptible. Hence, it is suggested that the tolerance-resistant nature of the NZB mice was inherent in T-cell precursors in the bone marrow and not in the host environment. Similar findings in support of this notion were also observed in BSXB mice. The significance of tolerance resistance in the development of autoimmunity is discussed. [ABSTRACT FROM AUTHOR]

The present studies reinvestigate the role of the T cell in the development of resistance to Listeria monocytogenes. Doubly thymus-deprived adult thymectomized irradiated bone marrow-reconstituted mice (D-AT × BM) were prepared using anti-theta serum-treated bone marrow from AT × BM donors for reconstitution. The growth of the bacteria in spleens and livers of D-AT × BM was inhibited and such animals survived infection with doses which were lethal to normal mice. Since the D-AT × BM animals were T cell-depleted. as evidenced by (a) absence of theta-positive cells in their spleens; (b) inability to mount a primary humoral response to a T-dependent antigen and (c) failure to reject H-2 incompatible skin allografts, their antibacterial resistance was not due to the presence of a residual T-cell population. Further evidence of T-cell depletion in these animals was furnished by the findings that, despite their resistance to L. monocytogenes, they failed to exhibit a delayed hypersensitivity reaction to Listeria antigens, their splenocytes were unable to transfer resistance to naive hosts and they did not develop an anamnestic response upon secondary challenge. We concluded from these findings that primary antibacterial resistance to L. monocytogenes need not necessarily depend on the development of specific cell-mediated immunity although under normal circumstances these two processes develop in chronological association. The increased resistance of D-AT × B M animals is interpreted as being due to the enhancement of bactericidal activity of mononuclear phagocytes, possibly caused by the removal of a regulatory T-cell population. This population seems to be radiosensitive and spleen-seeking and requires an intact spleen to mediate its effect. [ABSTRACT FROM AUTHOR]

Supernatants were obtained from cultures of keyhole limpet haemocyanin (KLH) primed mouse spleen cells, and also from cultures of KLH-educated, thymus-derived lymphocytes (T cells) after re-exposure of cells to the original priming antigen, KLH. These supernatants were able to facilitate the immune response of bone marrow-derived lymphocytes (B cells) to sheep erythrocytes (SRBC). Certain physical and biological properties of such supernatant activities are described. [ABSTRACT FROM AUTHOR]

There is substantial evidence from experiments of nature that immune competence plays a major part in determining the outcome of anogenital human papillomavirus (HPV) infection. Cellular rather than humoral immunity would appear to be the key to the control and eradication of HPV-induced warts. It seems likely that the HPV early proteins, which are responsible for viral replication (E1 and E2) and for promoting tissue proliferation (E6 and E7) will be the target antigens recognized by antigen-specific T cells. Natural infection is slow to produce an appropriate therapeutic immune response to these proteins, probably because HPV has adopted a strategy to prevent the effective presentation of viral antigens to the host immune system. Human papilomavirus infection is non-lytic so there is little release of viral antigen to professional antigen-presenting cells. Additionally no local pro-inflammatory cytokine production and no local inflammation is induced by HPV infection. An optimal therapeutic strategy for anogenital HPV infection would be, therefore, to accelerate the induction of a strong virus-specific immune response by inducing local inflammation and the cytokines necessary to invoke HPV-specific immunity. [ABSTRACT FROM AUTHOR]