Role of t lymphocytes in the humoral immune response. II. T cell-mediated regulation of antibody avidity.

The effect of activated T lymphocytes (ATC) on the avidity distribution of PFC in the secondary response was studied in normal mice. The total PFC response was not significantly changed for either direct or indirect PFC by administration of ATC before secondary antigen challenge. However, marked suppression occurred of indirect PFC that secreted high avidity antibody; no suppression was seen of high avidity direct PFC. At the same time, significant stimulation was seen of relative and absolute frequencies of indirect PFC that secreted middle and low avidity antibody. These effects were dependent on Thy 1-bearing, nylon nonadherent cells which demonstrated carrier specificity. In further characterization of these effects, it was found that increasing the number of ATC transferred produced progressive loss of high avidity PFC and compensatory increase in lower avidity PFC. Moreover, in these experiments, suppression of the high avidity response was inducible with the administration of ATC 5 weeks before to 3 days after the secondary immunization. Thus, it is likely that the avidity-modifying effects are dependent on T lymphocytes which influence the late stages of B lymphocyte maturation.     

Role of B cell antigen processing and presentation in the humoral immune response

In the 25 years since it was first indicated that lymphocyte subpopulations must interact during the generation of a humoral immune response, there has been an explosion of data on the molecular mechanism of this interaction. It has been demonstrated that T cells recognize a processed antigen fragment presented by a major histocompatibility complex molecule on the surface of an antigen-presenting cell. The minimal peptides required for T cell recognition of several proteins have been determined, the molecular genetics of many of the cell surface molecules involved have been defined, and the three-dimensional structure of the T cell receptor and the major histocompatibility antigens have been deduced. Several cell types have been found to act as antigen-presenting cells, although the roles of these populations in vivo remain unclear. However, it is clear that there must be a physical interaction between a B cell and a T cell before the B cell can respond to a T-dependent antigen. This interaction requires processing and presentation of the antigen by the B cell. Therefore this review focuses on antigen processing and presentation by resting B cells, one of the key steps in initiation of a humoral immune response.     

Role of the B-G-region antigen in the humoral immune response to the B-F-region antigen of chicken MHC

In the chicken MHC there exist two regions, designated F and G, which were separated by crossing-over. The F region contains genes controlling all functions characteristic of the MHC. So far only one gene has been assigned to the G region and it is responsible for the presence of an RBC antigen. When cross immunizing animals of the congenic lines CB and CC with erythrocytes, we have found that both F- and G-specific antibodies were produced. By using the recombinant haplotypes B ^R1 and B ^R2 we were able to dissociate the F from the G antigen and immunize with them separately. It was found that production of F antibodies required the copresence of the G antigen, whereas G antibodies were formed regardless of the presence or absence of the F-region antigen. It could be demonstrated that a prerequisite of the role of the G antigen with respect to the F antigen was the localization of both antigens on the same erythrocyte. Possible mechanisms underlying this phenomenon are discussed.Abbreviations used in this paper MHC major histocompatibility complex - RBC red blood cells - PBL peripheral blood lymphocytes - GVH graft-versus-host - MLR mixed lymphocyte reaction - i.v. intravenous - PBS phosphate-buffered saline - ME mercaptoethanol     

LPS regulation of the immune response: suppression of immune responses to orally administered T-independent antigen

The regulation of immune responses to gastrically administered TI antigens has been investigated, and the characterization of a regulatory cell population has been performed. Intragastric administration of TNP-haptenated homologous erythrocytes (TNP-MRBC) induced splenic IgM anti-TNP PFC responses in LPS nonresponsive C3H/HeJ mice that were higher than those in LPS-responsive C3H/HeN mice and similar to those noted in athymic (nu/nu) C3H/HeN animals. The simultaneous intragastric administration of LPS with TNP-MRBC augmented immune responses in a manner similar to that previously reported for parenterally administered LPS and antigen. Further, LPS-induced augmentation of TNP-MRBC responses was greater in athymic mice. These findings were substantiated using in vitro spleen cultures. Intragastric challenge with a 2nd TI antigen, TNP-LPS, induced approximately 8-fold higher splenic anti-TNP PFC responses in athymic C3H/HeN mice compared with those in euthymic littermates. By admixture of B and T cell populations, it was demonstrated that the host responsiveness to TNP-LPS was negatively regulated by suppressor cells. Suppressive activity resided in a Thy 1.2-bearing, irradiation-resistant, nylon wool-nonadherent cell population. These cells could be demonstrated in spleen and Peyer's patches from young or old LPS-responsive C3H/HeN mice, but not in tissues from LPS nonresponsive C3H/HeJ mice. The specificity of the regulator cells was not limited to TNP-LPS responses, since immune responsiveness to another TI antigen, TNP-dextran, was also under the control of this cell population. These studies confirm the TI nature of TNP-MRBC and indicate that immune responses to gastrically administered antigens such as TNP-LPS, TNP-dextran, and possibly TNP-MRBC are negatively regulated by a suppressor T cell population. A role for endogenous LPS in the generation of regulator cells and the effect of these cells on host responses to gut-derived antigens is discussed.     

Role of macrophages in the immune response to soluble protein antigen and in staphylococcal infection]

In experiments on rabbits immunized with soluble protein antigen immune reactions were found to be accompanied by the production of lipofuscin in macrophages. This process was the morphological manifestation of the digestion of antigen by macrophages which thus acquired the ability to migrate in the organ and to form lymphoid follicules in the medullary zone of lymph nodes. The newly formed follicules seem to be the basis of pronounced specific immune response. In staphylococcal bacteriemia the phagocytic activity of macrophages was delayed, thus causing disturbances in lipofuscin production; as a result, the subsequent phases of immune response also lagged somewhat behind in time.     

Deubiquitylation and regulation of the immune response

Ubiquitylation is a fundamental mechanism of signal transduction that regulates immune responses and many other biological processes. Similar to phosphorylation, ubiquitylation is a reversible process that is counter-regulated by ubiquitylating enzymes and deubiquitylating enzymes (DUBs). Despite the identification of a large number of DUBs, our knowledge of the function and activities of this family of enzymes is just starting to accumulate. As described in this Review, recent studies of several DUBs, in particular CYLD and A20, show that deubiquitylation has an important role in the regulation of both innate and adaptive immune responses.     

Role of exosomes in immune regulation

Exosomes are small vesicles originating from late endosomes, 30-100 nm in diameter with typical cup-shape morphology. They are reported to bear high levels of a narrow spectrum of molecules involved in immune response and signal transduction. Apart from removing obsolete membrane proteins, some surprising biological functions of exosomes were unveiled recently and their applications in immunotherapy of tumors are currently intensively investigated. Dendritic cell- (DC) and tumor-derived exosomes have considerable anti-tumor effects in experimental studies and several clinical trials. Despite their potential applications in eliciting a "positive" immune response, exosomes might induce some "unwanted" immune responses, such as immune tolerance and immune evasion. Therefore further investigations about the physiological functions of exosomes and the optimal way of exosome application in tumor immunotherapy are necessary. This review presents recent developments in the field of exosome research and focuses on its applications to tumor immunotherapy.     

Apoptosis, cross-presentation, and the fate of the antigen specific immune response

Induction of cell death by apoptosis, also called programmed cell death, and clearance of apoptotic bodies by scavenger cells has long thought to be an efficient means to dispose of unwanted cells without causing inflammatory responses able to mediate specific reactions. However, a number of evidences have been accumulated suggesting that apoptotic cell death is implicated in the pathogenesis of systemic and organ specific autoimmune diseases. In addition, recognition and engulfement of apoptotic cells by professional antigen presenting cells, such as dendritic cells, and their interaction with effector immune cells have been recently described to result in apoptotic cell-derived antigen specific tolerance. This review will summarise the most recent findings on the immunogenic potential of cells undergoing programmed death.     

"Cross-wiring" of the immune response in old mice: increased autoantibody response despite reduced antibody response to nominal antigen

Older humans and experimental animals have been repeatedly found to have higher titers of autoantibodies than do younger individuals despite the impaired responses of older individuals to foreign antigens. The studies reported here were designed to examine the relationship between these two age-related changes in antibody responses. Antibody response to foreign antigen was measured concurrently with autoantibody response in the same mice. Old mice (18-24 months old) had decreased responses to foreign antigens and increased responses to bromelain-treated syngeneic erythrocytes, compared to young mice (2 months old). In vitro mixing experiments were consistent with the possibility that suppressor cell activity in spleen cells from old mice reduce the antibody response to foreign antigen but not to autologous antigen. The results support an emerging view that age-associated changes in immune responses are the result of dysregulation rather than exhaustion of the immune system.     

Delayed advent of stringent, non-H-2 genetic regulation of the antibody response to a protein antigen.

The role of non-H-2 gene(s) in the control of the antibody response to three lysozymes was investigated. Upon secondary challenge, A/J (H-2a) mice generated at least a 25-fold greater anti-lysozyme plaque-forming cell response than did B10.A (H-2a) mice. Nearly equal, strong peak primary responses, predominantly IgG in nature, were obtained from both A/J and B10.A mice after a single challenge with lysozyme in complete Freund's adjuvant. However, clear differences in responses are seen within 5 days after the peak primary plaque-forming response and by day 28 at the serum antibody level. B10.A mice never equal their primary responses, whereas A/J mice demonstrate positive immune memory. It appears that a non-H-2 gene(s) that regulates the overall antibody level to a protein antigen becomes manifest only after an initial antibody response.     

Role of complement in the immune response

Evidence has accumulated that shows that fragments of C3 are potent inhibitors of immune responses. A low-molecular-weight fragment of C3 and fragments possessing leukocyte-mobilizing activity have been shown to block both antigen- and mitogen-induced human T cell proliferation, and to block mixed lymphocyte culture responses and the generation of cytotoxic lymphocytes. The same fragments inhibit the development of secondary in vitro antibody responses of rat lymphocytes. C3b can be shown to inhibit the polyclonal activation of human lymphocytes by pokeweed mitogen, but it has no effect on T cell proliferation or on the generation of cytotoxic T cells. We now propose that different C3 fragments selectively act on various lymphocyte subsets and thus play a profound role in regulating both immune effector functions and the intensity of the immune response.     

Cannabinoid receptors and the regulation of immune response

Cannabinoid research underwent a tremendous increase during the last 10 years. This progress was made possible by the discovery of cannabinoid receptors and the endogenous ligands for these receptors. Cannabinoid research is developing in two major directions: neurobehavioral properties of cannabinoids and the impact of cannabinoids on the immune system. Recent studies characterized the cannabinoid-induced response as a very complex process because of the involvement of multiple signalling pathways linked to cannabinoid receptors or effects elicited by cannabinoids without receptor participation. The objective of this review is to present this complexity as it applies to immune response. The functional properties of cannabinoid receptors, signalling pathways linked to cannabinoid receptors and the modulation of immune response by cannabinoid receptor ligands are discussed. Special attention is given to 'endocannabinoids' as immunomodulatory molecules.