Verification of immune response optimality through cybernetic modeling

An immune response cascade that is T cell independent begins with the stimulation of virgin lymphocytes by antigen to differentiate into large lymphocytes. These immune cells can either replicate themselves or differentiate into plasma cells or memory cells. Plasma cells produce antibody at a specific rate up to two orders of magnitude greater than large lymphocytes. However, plasma cells have short life-spans and cannot replicate. Memory cells produce only surface antibody, but in the event of a subsequent infection by the same antigen, memory cells revert rapidly to large lymphocytes. Immunologic memory is maintained throughout the organism's lifetime. Many immunologists believe that the optimal response strategy calls for large lymphocytes to replicate first, then differentiate into plasma cells and when the antigen has been nearly eliminated, they form memory cells. A mathematical model incorporating the concept of cybernetics has been developed to study the optimality of the immune response. Derived from the matching law of microeconomics, cybernetic variables control the allocation of large lymphocytes to maximize the instantaneous antibody production rate at any time during the response in order to most efficiently inactivate the antigen. A mouse is selected as the model organism and bacteria as the replicating antigen. In addition to verifying the optimal switching strategy, results showing how the immune response is affected by antigen growth rate, initial antigen concentration, and the number of antibodies required to eliminate an antigen are included.     

Optimal strategies in immunology

Summary The optimal strategy available to the immune system for responding to a non-replicating thymus-independent antigen is examined. By applying Pontryagin's maximum principle to a set of mathematical models of lymphocyte populations and their antibody production, it is found that the optimal strategy of bang-bang control appears robust. In a variety of structurely related biological models, similar behaviour is observed.The models that we consider assume that antigen triggers a population of B-lymphocytes. These triggered lymphocytes can either proliferate and secrete modest amounts of antibody or differentiate into nondividing plasma cells which secrete large amounts of antibody. For biologically reasonable parameter values it is found that for low doses of antigen, immediate differentiation into plasma cells is optimal, while for high antigen doses a proliferative state followed by differentiation is the best strategy.Work performed under the auspices of the U. S. Energy Research Development Administration.Work supported by NSF Grant No. BMS 75-18897.     

The making of a professional secretory cell: architectural and functional changes in the ER during B lymphocyte plasma cell differentiation

B lymphocytes are small cells that express antigen receptors and secrete little if any IgM. Upon encounter with antigen, they differentiate into short-lived plasma cells, which secrete large amounts of polymeric IgM. Plasma cell differentiation entails a massive development of the endoplasmic reticulum to sustain high levels of Ig production. Recent findings suggest a role for the unfolded protein response in orchestrating the architectural and functional changes during terminal plasma cell differentiation.     

Antigen modulation of the immune response: IV. Selective triggering of antibody production and memory cell proliferation

When memory cells are transferred to syngeneic irradiated recipients and then challenged at various times after transfer, a precipitous decline in the ability of these cells to mount a secondary response is seen. Using this model we have investigated some of the influences which antigen can exert on the memory cell population. The results indicate that antigen may: 1) either stimulate the memory cells to proliferate and form new memory cells or stimulate memory cells to become antibody forming cells and 2) selectively trigger the memory cells for low or high affinity antibody production. This selective antigen triggering appeared to depend upon its concentration: high dose antigen challenge led to the production of large amounts of lower affinity antibody but stimulated less memory cell proliferation while low dose challenge showed just the opposite. Control experiments indicated that recruitment of new memory cells from a virgin precursor population was not responsible for these observations. Our results thus suggest that an asymmetrical division of memory cells is occurring in which antigen can exert selective influences in much the same way as seen with virgin precursor cells.     

Optimal strategies in immunology III. The IgM-IgG switch

Summary During a primary immune response generally two classes of antibody are produced, immunoglobulin M (IgM) and immunoglobulin G (IgG). It is currently thought that some lymphocytes which initially produce IgM switch to the production of IgG with the same specificity for antigen. During a secondary immune response IgG is the predominant antibody made throughout the response. In this paper we address the question of why such apparently complicated modes of response should have been adapted by evolution.We construct mathematical models of the immune response to growing antigens which incorporate complement dependent cell lysis. By comparing the times required to eliminate antigen we show that under certain conditions it is advantageous for an animal to switch some of its lymphocytes from IgM to IgG production during a primary response, but yet to secrete only IgG during a secondary response. The sensitivity of such a conclusion to parameter variations is studied and the biological basis and implications of our models are fully discussed.Portions of this work were performed under the auspices of the U.S. Department of Energy. A.S.P. was also supported by the National Science Foundation under Grant No. ENG-7904852 and BRSG grant S07 RR05664-11 awarded by the Biomedical Research Support Grant Program, Division of Research Resources, National Institute of Health. A.S.P. is the recepient of an NIH Research Career Development Award 1K04 AI 00357-01. S.R. was a recipient of NIH Fellowship 5 F32 AI05107-02     

Simian virus 40 large-T-antigen-specific rejection of mKSA tumor cells in BALB/c mice is critically dependent on both strictly tumor-associated, tumor-specific CD8(+) cytotoxic T lymphocytes and CD4(+) T helper cells

Protective immunity of BALB/c mice immunized with simian virus 40 (SV40) large T antigen (TAg) against SV40-transformed, TAg-expressing mKSA tumor cells is critically dependent on both CD8(+) and CD4(+) T lymphocytes. By depleting mice of T-cell subsets at different times before and after tumor challenge, we found that at all times, CD4(+) and CD8(+) cells both were equally important in establishing and maintaining a protective immune response. CD4(+) cells do not contribute to tumor eradication by directly lysing mKSA cells. However, CD4(+) lymphocytes provide help to CD8(+) cells to proliferate and to mature into fully active cytotoxic T lymphocytes (CTL). Depletion of CD4(+) cells by a single injection of CD4-specific monoclonal antibody at any time from directly before injection of the vaccinating antigen to up to 7 days after tumor challenge inhibited the generation of cytolytic CD8(+) lymphocytes. T helper cells in this system secrete the typical Th-1 cytokines interleukin 2 (IL-2) and gamma interferon. Because in this system TAg-specific CD8(+) cells secrete only minute amounts of IL-2, it appears that T helper cells provide these cytokines for CD8(+) T cells. Moreover, this helper effect of CD4(+) T cells in mKSA tumor rejection in BALB/c mice does not simply improve the activity of TAg-specific CD8(+) CTL but actually enables them to mature into cytolytic effector cells. Beyond this activity, the presence of T helper cells is necessary even in the late phase of tumor cell rejection in order to maintain protective immunity. However, despite the support of CD4(+) T helper cells, the tumor-specific CTL response is so weak that only at the site of tumor cell inoculation and not in the spleen or in the regional lymph nodes can TAg-specific CTL be detected.     

The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response.

Immunization with protein-containing antigens results in two types of antigen-specific B cell: antibody forming cells (AFCs) producing antibody of progressively higher affinity and memory lymphocytes capable of producing high affinity antibody upon re-exposure to antigen. The issue of the inter-relationship between affinity maturation of memory B cells and AFCs was addressed through analysis of single, antigen-specific B cells from the memory and AFC compartments during the primary response to a model antigen. Only 65% of splenic memory B cells were found capable of producing high affinity antibody, meaning that low affinity cells persist into this compartment. In contrast, by 28 days after immunization all AFCs produced high affinity antibody. We identified a unique, persistent sub-population of bone marrow AFCs containing few somatic mutations, suggesting they arose early in the response, yet highly enriched for an identical affinity-enhancing amino acid exchange, suggesting strong selection. Our results imply that affinity maturation of a primary immune response occurs by the early selective differentiation of high affinity variants into AFCs which subsequently persist in the bone marrow. In contrast, the memory B-cell population contains few, if any, cells from the early response and is less stringently selected.     

Activation of B cells by non-canonical helper signals

Cognate interaction between T and B lymphocytes of the adaptive immune system is essential for the production of high-affinity antibodies against microbes, and for the establishment of long-term immunological memory. Growing evidence shows that-in addition to presenting antigens to T and B cells-macrophages, dendritic cells and other cells of the innate immune system provide activating signals to B cells, as well as survival signals to antibody-secreting plasma cells. Here, we discuss how these innate immune cells contribute to the induction of highly diversified and temporally sustained antibody responses, both systemically and at mucosal sites of antigen entry.     

Immunological memory is compromised by food restriction in deer mice Peromyscus maniculatus

The immune system protects organisms against infection, but this protection presumably comes at a cost. Here, we asked whether food restriction would compromise the ability of an organism to generate an immune response on reexposure to an antigen, which would represent a functional cost of immunological memory. Immunological memory is generated when B and T lymphocytes sensitive to components of pathogens (i.e., antigens) proliferate after exposure and persist in circulation to hinder reinfection. To test the possibility that B cell memory, the component of the immune system responsible for antibody production, is expensive to maintain, secondary antibody production against a novel protein [keyhole limpet hemocyanin (KLH)] was compared in food-restricted and ad libitum-fed male deer mice (Peromyscus maniculatus). To determine whether compromised secondary antibody production was solely due to elevated corticosterone independent of resource availability, some food-restricted and ad libitum-fed mice were subjected to unpredictable, chronic (2 h/day) restraint. Mice fed 70% of their ad libitum diet 2 wk after primary antigen challenge produced approximately 95% less IgG against KLH after a second antigen challenge than mice fed ad libitum, even though all mice were fed ad libitum during the secondary antibody response period. Restraint had no effect on secondary IgG production in response to KLH, and corticosterone concentrations 1 day after food restriction did not differ between food-restricted and ad libitum-fed mice. Together, these data imply that secondary antibody responses and the benefits of immunological memory are energetically costly in this species.     

Contributions of memory B cells to secondary immune response

The secondary immune response is one of the most important features of immune systems. During the secondary immune response, the immune system can eliminate the antigen, which has been encountered by the individual during the primary invasion, more rapidly and efficiently. Both T and B memory cells contribute to the secondary response. In this paper, we only concentrate on the functions of memory B cells. We explore a model describing the memory contributed by the specific long-lived clone which is maintained by continued stimulation with a small amount of antigens sequestered on the surfaces of the follicular dendritic cells (FDC). The behavior of the secondary response provided by the model can be compared with experimental observations. The model shows that memory B cells indeed play an important role in the secondary response. It is found that a single memory cell in a long-lived clone may not be long-lived. In the present note, the influences of relevant parameters on the secondary response are also explored.     

Polyclonal activation of murine B lymphocytes by immune complexes

Murine splenic B lymphocytes are stimulated by homologous immune complexes to proliferate and secrete polyclonal antibody. The use of antibody from whole serum or monoclonal antibodies to form complexes resulted in the stimulation of mouse B lymphocytes. The ratio of antibody to antigen appears to be critical for the generation of the polyclonal antibody response. Because antigen and antibody are added independently at culture initiation, the exact nature of the complex is unknown, but optimal polyclonal antibody formation occurs in slight antigen excess. Immune complex-induced polyclonal antibody production requires the presence of both macrophages and T cells, whereas B cell proliferation requires only macrophages. The role of the macrophage appears to be to cleave a low m.w. (17,000) fragment from the complex, which is responsible for lymphocyte activation.     

The immune response to agents that cause acute and chronic diseases

Recent advances in lymphocyte technology allow production of large amounts of homogenous T cells which create immunoregulatory peptides. This means that it is now possible to define and purify nontoxic peptides that either specifically turn off or turn on immune responses. For example, monoclonal peptides synthesized by inducer cells each activates a different target cell to divide or differentiate. One activates stem cells to differentiate into red cells and white cells [27], another stimulates B cells to secrete antibody [21], and another induces mast cells to divide [26] and perhaps to differentiate. More recent work has shown that some inducer peptides may "fine tune" the immune response: Certain types of inducer clones, for example, selectively stimulate production of IgA. Peptides that mediate the activity of these clones are the subject of intense analysis of because these monoclonal substances offer the possibility of stimulating rapid induction of IgA after infection by microbes that enter through mucosal of the gut, bladder or lungs. This type of antibody (IgA) is the body's key defense against infections by these microbes: Development of a rapid and specific IgA response is the most important factor in the outcome of infections by viruses such as genital herpes type II and infections by intracellular bacterial pathogens that are currently resistant to treatment by antibiotics. Perhaps the most informative point that has come from these studies is that each peptide that has been isolated from T cell clones exerts powerful regulatory effects on either the intensity or type of the immune response. The hope is that some of these immunoregulatory molecules or their analogs can be used as potent therapeutic agents for some chronic diseases. Since purified inducer and suppressive peptides will be available in large amounts within the next several years, it will not be long before this strategy can be thoroughly evaluated.     

B lymphocyte regulation of the immune system. I. In vivo biologic activity of the novel lymphokine, B cell-derived enhancing factor (BEF)

B cell-derived enhancing factor (BEF) is a lymphokine of B cell origin which was originally identified and characterized by its ability to enhance in vitro antibody responses, an effect shown to be due to the ability of BEF to reduce the activation of suppressor T cells. The present study was undertaken to determine whether BEF could also be active in modulating antibody responses in vivo. The data presented here demonstrate that BEF is biologically active in vivo, as manifested by significantly enhanced primary IgM and IgG antibody responses in mice that were either injected with BEF prepared exogenously or implanted with growing BEF-secreting cells of a B cell line. Moreover, BEF was shown to enhance subsequent development of immunologic memory in mice pretreated with BEF at the time of primary immunization; these mice then displayed enhanced secondary responses when challenged with the same antigen some weeks later. The mechanism by which BEF exerts biologic activities to positively modulate in vivo antibody responses and immunologic memory reflects the ability of BEF to modulate one or more T cell functions, as evidenced by the following findings. 1) Transient in vitro exposure to BEF of T cells, but not of B cells, endowed such cells with the capacity to adoptively transfer enhanced primary antibody responses to irradiated recipients. 2) Utilizing adoptive in vivo antibody responses, in which fractionated B cell or T cell populations were obtained from BEF-pretreated mice, revealed that one effect of BEF which results in enhanced immunologic memory is related to its activity on T cells during the priming phase of the immune response. Finally, the existence of this B cell-derived lymphokine and the demonstration of its in vivo regulatory effects on the immune system provide yet another example of the emerging biologic importance of B lymphocytes in the overall regulation of the immune system.     

Memory and CAR-NK cell-based novel approaches for HIV vaccination and eradication

Human immunodeficiency virus (HIV) is one of the critical infectious agents with thousands of newly infected people worldwide. High mutational capability and rapid diversification, inhibition of humoral and cellular immune responses, and thus inability for recognition of an immunogenic region in the viral envelope by the immune system are major challenges. Natural killer (NK) cells are multifunctional, playing a key role in the identification and elimination of HIV-infected cells. These cells identify and eliminate virus-infected cells in a multilateral manner, such as ligand stress, antibody-dependent cell cytotoxicity (ADCC), T follicular helper (Tfh), and the activation of most of the stimulatory receptors. Moreover, these cells release cytokines leading to the activation of cytotoxic lymphocytes (CTLs) and dendritic cells (DCs), contributing to efficient viral elimination. Some subsets of NK cells exhibit putatively enhanced effector functions against viruses following vaccination easily expanded and identified by NK cell lines culture. Furthermore, NK cells promote the elimination of HIV-infected cells which reduce the expression of major histocompatibility complex (MHC) molecules. Memory NK cells have higher functionality and renewable potential. A pioneering strategy to establish an efficacious HIV vaccine would include stimulation of the accumulation and long-term maintenance of these HIV-reactive NK cells. CAR-NK (chimeric antigen receptor-natural killer) cells-based antiviral therapies have emerged as novel approaches with the ability of antigen recognition and more advantages than CAR-T (chimeric antigen receptor-T) cells. Recent development of induced pluripotent stem cell (iPSC)-derived NK cells with enhanced activity and efficiency conferred a promising insight into CAR-NK cell-based therapies. Therefore, memory and CAR-NK cells-based approaches can emerge as novel strategies providing implications for HIV vaccine design and therapy.     

Transition in the Character of Immunological Memory in Mice after Immunization

The immunological memory in antibody response of mice to bovine serum albumin was investigated at the level of IgM and IgG antibody-forming cells. The antigen at a dose much lower than required for eliciting a detectable level of the primary antibody response could latently activate the immune machinery to an extent adequate for specific recall, whereas higher doses of antigen were effective in evoking strong anamnestic response. The potentiality to develop the anamnestic response was found even in the latent phase of the primary antibody response and was maintained for more than 2 months. The immunological memory acquired in an early phase after the primary immunization mainly involved IgM antibody response and late memory concerned IgG response.     

Reovirus intermediate subviral particles constitute a strategy to infect intestinal epithelial cells by exploiting TGF‐β dependent pro‐survival signaling

Intestinal epithelial cells (IECs) constitute the primary barrier that separates us from the outside environment. These cells, lining the surface of the intestinal tract, represent a major challenge that enteric pathogens have to face. How IECs respond to viral infection and whether enteric viruses have developed strategies to subvert IECs innate immune response remains poorly characterized. Using mammalian reovirus (MRV) as a model enteric virus, we found that the intermediate subviral particles (ISVPs), which are formed in the gut during the natural course of infection by proteolytic digestion of the reovirus virion, trigger reduced innate antiviral immune response in IECs. On the contrary, infection of IECs by virions induces a strong antiviral immune response that leads to cellular death. Additionally, we determined that virions can be sensed by both TLR and RLR pathways while ISVPs are sensed by RLR pathways only. Interestingly, we found that ISVP infected cells secrete TGF‐β acting as a pro‐survival factor that protects IECs against virion induced cellular death. We propose that ISVPs represent a reovirus strategy to initiate primary infection of the gut by subverting IECs innate immune system and by counteracting cellular‐death pathways.     

A CD8+ T cell clone specific for antigen also recognizes peptidomimics present in anti-idiotypic antibody: implications for T cell memory

The relay hypothesis [R. Nayak, S. Mitra-Kaushik, M.S. Shaila, Perpetuation of immunological memory: a relay hypothesis, Immunology 102 (2001) 387-395] was earlier proposed to explain perpetuation of immunological memory without requiring long lived memory cells or persisting antigen. This hypothesis envisaged cycles of interaction and proliferation of complementary idiotypic B cells (Burnet cells) and anti-idiotypic B cells (Jerne cells) as the primary reason for perpetuation of immunological memory. The presence of peptidomimics of antigen in anti-idiotypic antibody and their presentation to antigen specific T cells was postulated to be primary reason for perpetuation of T cell memory. Using a viral hemagglutinin as a model, in this work, we demonstrate the presence of peptidomimics in the variable region of an anti-idiotypic antibody capable of functionally mimicking the antigen derived peptides. A CD8+ CTL clone was generated against the hemagglutinin protein which specifically responds to either peptidomimic synthesizing cells or peptidomimic pulsed antigen presenting cells. Thus, it appears reasonable that a population of activated antigen specific T cells is maintained in the body by presentation of peptidomimic through Jerne cells and other antigen presenting cells long after immunization.     

In vitro immune response by murine bone marrow cells stimulated against soluble immune complexes.

Synchronized nonadherent bone marrow lymphocytes were stimulated with soluble immune complexes, in antigen excess formed by C3H/HeJ antibodies and various noncross-reacting protein antigens, in a suspension culture which allowed longterm cultivation. On binding of these complexes, lymphocytes underwent blast transformation with mitosis and formation of plasma cells which secreted specific antibodies to the antigen; a cyclic sequence of lymphocytes, blasts, and plasma cells was observed until the majority of the cell population appeared to be plasma cells. The relative percentage of mature plasma cells then decreased leaving mostly small lymphoid cells among which evidence suggests the presence of memory cells. Complexes at equivalence stimulated for the first few days, whereas antibody excess caused stimulation only initially followed by inhibition of the response. Antibodies passively added to the cultures inhibited the proliferative reaction; free antigen induced a typical secondary-type response.     

抗独特型抗体与T细胞记忆的关系

记忆T细胞作为人体免疫系统中的一个组成部分,在免疫应答中发挥着至关重要的作用,因此利用抗独特型抗体制备诱导产生记忆T细胞的疫苗是免疫学领域的一个重要方向。抗独特型抗体Fab段具有与特异性抗原相似的抗原决定簇的结构,其作为抗原替代物制备的疫苗所激发机体产生的记忆T细胞具有特异性强和安全性高的特点,成为一种比较理想的疫苗.就抗独特型抗体与T细胞记忆之间的联系及其应用效果作一简要综述。     

Use of Human CD4 Transgenic Mice for Studying Immunogenicity of HIV-1 Envelope Protein gp120

HIV-1 envelope protein, gp120, is a major immunogenic protein of the AIDS virus. A specific feature of this protein is its interaction with the receptor protein, human CD4, an important component of the immune system. This interaction might affect the immunogenic properties of the gp120 and modulate the immune response towards HIV. To test this hypothesis we used human CD4-transgenic mice for immunization with gp120. The dynamics of the immune response towards gp120, CD4 and other proteins was followed. The results show that the primary immune response to gp120 (two weeks) developed somewhat faster in CD4-transgenic mice versus non-transgenic mice. Both animals, however, ultimately mounted the same level of response over time. The primary immune response to gp120 when complexed with soluble CD4 before the immunization, developed similarly in both groups. The secondary immune response was earlier and markedly stronger in non-transgenic mice compared with the transgenic mice where a less efficient memory response to gp120 was observed. The ability of gp120 to directly interact with CD4+ helper lymphocytes appears to affect the humoral response towards this antigen. Moreover, these effects illustrate how viral modulation of these cells may in turn lead to potentially different states of immunological equilibrium.