Cell death recognition model for the immune system

It is essential for the immune system to recognize markers or understand rules required for discriminating antigens that should be actively responded to from those be tolerated. Although the classic self-nonself theory over the past five decades has been challenged by "danger" model and "infectious nonself" model, etc., no theories could fit for all. Cell death is important not only for its role in homeostasis, but also for its decisive effects on the immune responses. Different ways of cell death, apoptosis or necrosis, transmit fundamentally opposite driving forces for the immune system, inducing tolerance or initiating adaptive immune responses. The progress in understanding phagocytosis and process of apoptotic and necrotic cells leads the author to propose "cell death" recognition model for the immune system. Four principles are important in this model. First, only antigens shedding from apoptotic or necrotic cells rather than those from healthy cells, can be presented to na?ve T cells. Second, either apoptotic cells or necrotic cells, but not healthy cells, can attract phagocytes, namely dendritic cells (DC) or macrophages that are also antigen presenting cells (APC), to scavenge dead cells. Third, macrophages or DC residing in non-lymphoid tissues phagocytose dying/dead cells, migrate to lymphoid tissues and present antigens to na?ve T cells there. Fourth, tolerance or adaptive responses are not dependent on whether the antigens are self or nonself, but on the ways of cell death during antigen presentation. Importantly, tolerance and adaptive immunity are all dominant responses and the impact of cell death on immune responses is a dynamic balance between them. "Cell death" recognition model could more easily explain various immune phenomena, including infection, self tolerance and autoimmunity, tumor immunity as well as transplant rejection. Investigation into the roles and mechanisms of cell death mediated immune responses and finding out key modulators will prompt better understanding the ways of immune recognition and provide novel strategies for the management of autoimmunity, tumors, infections as well as transplantation.     

The immune system in chickens

The most sophisticated feature of the immune system expressed in vertebrates is recognition of foreign molecules by distinct types of immunocompetent cells. Birds are the first vertebrates in which a clear dichotomy of the lymphoid system has been established: 1. Thymus-derived (T) lymphocytes, the effector cells in cell-mediated (immunity and 2. Bursa-derived (B) lymphocytes, the precursor cells of the antibody-synthesizing plasma cell. Lymphocyte differentiation begins with the migration of haemopoietic stem cells from yolk sac and liver into bursa and thymus early in embryonic life followed by clonal expansion within the central lymphoid tissues. The second stage of differentiation is considered to begin with the migration of lymphocytes to the peripheral lymphoid tissue (spleen and lymph nodes). Based on genetic information, B cells are capable of recognizing foreign antigens by specific immunoglobulin molecules whereas T cell receptors are presumed to be products of the immune response genes. Surface differences provide the basis for analyzing the population dynamics of T and B cells and the pathway of immunologic diseases as well. There is compelling evidence that antigen entering the body stimulates a conventional type of systemic immune response. Antigen which remains in the mucosa, however is apt to induce a local type of response. The responses include B cells, which remain in the peripheral lymphoid tissues for the most part, and secrete immunoglobulins of different classes (IgM, IgG, IgA). T cells, however, are represented by the circulating pool of lymphocytes, and do not synthesize antibodies but instead release various mediators upon interaction with the antigen, which play a role in cell-mediated immunity. The antibody response to most antigens requires cooperation between T and B cells and macrophages as well, but in some instances T cells can also suppress B cell function. There is some evidence that the immune response of chickens is genetically controlled, which is particularly pertinent to susceptibility and resistance to diseases. Since humoral and cell-mediated immunity can separately be affected by removal of central lymphoid organs, chickens may serve as a useful model to elucidate the function of the immune system in health and disease.     

Interactions of T lymphocytes with human vascular endothelial cells: role of endothelial cells surface antigens

We have studied the interactions of peripheral blood T lymphocytes with cultured human vascular endothelial cells, focusing upon endothelial cell surface antigens important for T cell recognition. Under standard culture conditions endothelial cells express class I but not class II major histocompatibility complex (MHC) antigens. However, class II antigens may be induced by activated T cells or T cell products, including the lymphokine immune interferon. Immune interferon concomitantly increases class I antigen expression and causes a change in cell shape. In addition to vascular endothelial cells, we have found that vascular smooth muscle cells and human dermal fibroblasts may also be induced by immune interferon to express class II antigens. All known human class II antigens are induced (i.e. HLA-DR, DC and SB) as is the associated invariant chain. Induced antigen expression in these cells is stable over several days, although mRNA levels decline rapidly upon withdrawal of interferon. Vascular and stromal cell class II antigens are functional, in that they can be recognized by cytolytic and helper T cell clones. Several non-MHC antigens are also involved in the recognition of endothelial and stromal cells by T cells. We propose a model for the role of inducible class II molecules on endothelium and stromal cells in vivo: The induction of class II MHC antigens on endothelial cells, locally mediated by activated T cells, enables endothelium to present an immunogenic cell surface structure, comprised of antigen plus self class II polymorphic determinants, which in turn, serves to recruit additional antigen-specific T cells from the circulation into the site of a developing cell mediated immune response. Class II molecules on stromal cells, also induced locally at the site of a developing response, confers immune accessory function on these cells and may serve to augment and sustain a T cell response.     

Antigen processing in the mucosal immune system.

The mucosal immune system is concerned with host defense along the moist surfaces of the body which have contact with the external environment. These sites contain specialized lymphoid structures which contain precursors for IgA-synthesizing B lymphocytes and immunoregulatory T lymphocytes which will determine whether oral tolerance or a strong immune response develops against antigens administered orally. The key step to antigen processing in the gastrointestinal tract involves its initial uptake from the gut lumen by specialized follicle associated epithelium called 'M' cells. M cells originate from adjacent crypt epithelium and are interspersed between the absorptive epithelial cells in the follicle-associated epithelium. M cells cells have short, irregular microvilli, are closely associated with lymphocytes, do not have a prominent terminal web, and have only weak alkaline phosphatase activity but strong nonspecific esterase activity. M cells do not express surface MHC class II (HLA-DR) antigens. These cells take up macromolecules, viruses, bacteria and protozoa within 30 minutes from the initial presentation of the antigen to the intestinal lumen. After the initial uptake of antigen by M cells, the antigens are transported into the follicular areas to be processed by dendritic cells and brought into close contact with the antigen-specific precursors for IgA secreting plasma cells. The final result of M cell processing is the production of a vigorous secretory IgA response and local cell-mediated immunity with suppression of a systemic IgG, IgE and delayed-type hypersensitivity to orally-administered antigens.     

Immunological functions of the gut--role of the mucosal immune system

This review summarizes recent information about immune responses in the intestinal mucosa with emphasis on the role of orally-administered antigens from the external environment. The intestinal mucosa provides an extensive surface for potential absorption of pathogenic environmental antigens, such as microbes, chemicals, and food. The intestinal mucosa is densely populated by IgA-producing plasma cells. The humoral immune responses to antigens in the intestinal mucosa are largely of the IgA class in secretory form (sIgA). This sIgA provides an immunological barrier to absorption of antigens on the mucosal epithelium and to penetration into the body. The cell-mediated immune mechanism is also equipped in the mucosal sites. In addition, the mucosal immune response induces hyporesponsiveness of nonmucosal (systemic) immune reactions, and the liver is an integral part of the mucosal immune system. Thus we consider that the mucosal immune system plays a central role in the maintenance of the homeostasis of the total immune system.     

Nature of tumour rejection antigens in ovarian cancer

Major progress in the analysis of human immune responses to cancer has been made through the molecular characterization of human tumour antigens. The development of therapeutic strategies for eliciting immune‐mediated rejection of tumours has accelerated due to the elucidation of the molecular basis for tumour cell recognition and destruction by immune cells. Of the various human tumour antigens defined to date in ovarian cancer, the cancer‐testis (CT) family of antigens have been studied extensively preclinically and clinically because of their testis‐restricted expression in normal tissues and ability to elicit robust immune responses. Recent developments in cancer sequencing technologies offer a unique opportunity to identify tumour mutations with the highest likelihood of being expressed and recognized by the immune system. Such mutations, or neoantigens, could potentially serve as specific immune targets for T‐cell‐mediated destruction of cancer cells. This review will highlight current work in selecting tumour rejection antigens in ovarian cancer for improving the efficacy of immunotherapy.     

The effects of cyclosporin A on the chicken immune system

Some aspects of the effects of cyclosporin A (CsA) on the chicken immune system are described. High serum levels of CsA could be maintained by i.m. administration of the drug in a neutral oil (Miglyol 812) every three days. After a transient decrease in peripheral blood T lymphocytes, the blood picture remained normal over a dosage period of three weeks. Mitogenic stimulation of the peripheral blood lymphocytes was strongly depressed, however. Whereas there was a trend to decreased primary immune response of T-dependent (sheep red blood cells, human γ-globulins) and T-independent (B. abortus) antigens, high variation in individual response made this trend statistically insignificant, except for the response to B. abortus at a CsA dose of 50 mg/kg. There was also a trend to decreased secondary IgM response to T-dependent antigens and increased IgM response to the T-independent antigens. The clearest alteration in secondary humoral response was the block of IgG (+ IgA) response to both categories of antigens. There was only a slight decrease in body weight after 3 weeks of CsA administration, a decrease in the absolute weights of thymus and spleen (but not bursa) at 50 mg/kg and a decrease in relative weight only in the case of the thymus. Despite these changes, the histology of the thymus, particularly the cortex, was normal. The major histological changes were in the spleen where there was a depletion of the periarteriolar lymphytic sheath, a marked increase in granulated cells, a decrease in germinal centers, and the appearance of large numbers of Mott cells. This type of cell was occasionally found in bone marrow and very rarely in liver and the mucosal connective tissue of the bursa, tissues which were otherwise normal. The Mott cell may arise as a result of the changes in T cell subsets leading to an uncontrolled production of nonsecreted immunoglobulins.     

Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response

The lymphoid organs contain specialized microanatomic structures composed of lymphoid, myeloid and stromal cells that are vital to the generation of an effective adaptive immune response. Although the existence of these specialized structures has been known for over a century, the developmental signals that generate them and the specific roles of these structures in the immune response have remained largely elusive. Because of their position adjacent to the marginal sinuses, marginal zone B (MZB) cells are amongst the first population of cells seen by blood born antigens and are presumed to have a critical role in host defense against bacterial pathogens. Here we demonstrate that a deficiency of the tyrosine kinase (Pyk-2) results in a cell autonomous defect of MZB cell production. In response to repetitive polysaccharide antigens (T-independent type II (TI-II)) Pyk-2-deficient mice displayed marked suppression of IgM, IgG3 and IgG2a production. Furthermore, complement receptor engagement proved necessary for the specific targeting of polysaccharide antigens to MZB cells. These results suggest how innate immune responses mediated through complement coupling are translated into an adaptive response by MZB cells, and provide a potential mechanism for the T cell independence of humoral responses to polysaccharide antigens.     

Minor histocompatibility antigens: targets for tumour therapy and transplant tolerance

Minor histocompatibility (H) antigens are allogeneic targets of T-cell mediated immune reactivity following allogeneic haematopoietic stem cell transplantation. Depending on the tissue expression profile of the minor H antigens this immune reactivity clinically results in graft-vs-host disease or in graft-vs-leukaemia effects. Targeting haematopoietic-specific minor H antigens by adoptive immunotherapy will evoke leukaemia-specific allo-immune responses, thereby enhancing graft-vs-leukaemia effects. Recently, a novel alternative role for minor H antigens in transplantation has been described; minor H antigen-specific T cells appear to be able to regulate allo-immune responses after solid organ transplantation. This diversity in immune reactivity suggests a broad clinical potential of minor H antigens, both in haematopoietic stem cell transplantation and in solid organ transplantation.     

Viral Oncolysates as Human Tumor Vaccines

Postoncolytic immunity entails immune reactions acquired through an oncolytic virus infection or through repeated immunizations with viral oncolysates (or virally modified tumor cell membranes) that are valid and operational also against virally not modified tumor cells of the same type. NK cells react to budding virions, induce target cell lysis primarily but not exclusively by the production of granzymes and pore-forming proteins and operate without direction from memory cells. In contrast, immune T cells (including some TIL) are MHC-restricted, act under the direction of memory cells and lyse target cells primarily but not exclusively by the release of lymphotoxin (TNFβ) causing programmed cell death (apoptosis) through endonuclease activation and target cell DNA fragmentation. This author proposes that it is not NK, but the immune T cells that mediate postoncolytic immunity. Oncogene amplification may protect immortalized tumor cells even when expressing peptide antigens through MHC molecules against lymphotoxin-mediated apoptosis; but virally-infected tumor cells releasing budding virions remain susceptible to NK cells. Highly immunogenic viral oncolysates should present both budding virions for NK cells and processed viral and tumoral peptide antigens co-jointly for immune T cells.     

Viral oncolysates as human tumor vaccines.

Postoncolytic immunity entails immune reactions acquired through an oncolytic virus infection or through repeated immunizations with viral oncolysates (or virally modified tumor cell membranes) that are valid and operational also against virally not modified tumor cells of the same type. NK cells react to budding virions, induce target cell lysis primarily but not exclusively by the production of granzymes and pore-forming proteins and operate without direction from memory cells. In contrast, immune T cells (including some TIL) are MHC-restricted, act under the direction of memory cells and lyse target cells primarily but not exclusively by the release of lymphotoxin (TNF beta) causing programmed cell death (apoptosis) through endonuclease activation and target cell DNA fragmentation. This author proposes that it is not NK, but the immune T cells that mediate postoncolytic immunity. Oncogene amplification may protect immortalized tumor cells even when expressing peptide antigens through MHC molecules against lymphotoxin-mediated apoptosis; but virally-infected tumor cells releasing budding virions remain susceptible to NK cells. Highly immunogenic viral oncolysates should present both budding virions for NK cells and processed viral and tumoral peptide antigens co-jointly for immune T cells.     

Forcing Tumor Cells to Present Their Own Tumor Antigens to the Immune System： a Necessary Design for an Efficient Tumor Immunotherapy

The general principle for tumor cells to escape from immune surveillance is to prevent tumor antigens from being recognized by the immune system. Many methods have been developed to increase the immunogenecity of the tumor cells. The most efficient methods are able to force tumor cells to present their own tumor antigens to the immune system. Stimulating Th cells by converting tumor cells into MHC class II /Ii- antigen presenting cells is one of the most efficient technologies. Using antisense methods, we suppress the expression of the Ii protein that normally co-expresses with MHC class II molecules and blocks the antigenic peptide binding site of MHC class II molecules during synthesis in the endoplasmic reticulum. In such tumor cells, the“unprotected“ MHC class II molecules pick up endogenous tumor antigenic peptides, which have been transported into the ER for binding to MHC class I molecules. Simultaneous presentation of tumor antigens by both MHC class I and II molecules generates a robust and long-lasting anti-tumor immune response. MHC class II /Ii- tumor cells are potent tumor cell vaccines and also cure a significant number of animals with renal and prostate tumors. We have developed analogous human gene vectors that are suitable for most patients and cancers.     

Tolerance and immunity in the intestinal immune system

The intestinal immune system must guard the body against invasion by pathogens while avoiding a response to the many potential antigens present in food. In the absence of the inflammatory stimuli necessary to elicit an immune response, oral administration of soluble protein antigens induces antigen-specific systemic nonresponsiveness. Recent studies have shown that peripheral nonresponsiveness to orally administered antigen is preceded by transient T-cell activation and is due primarily to the induction of functional T-cell anergy. The microenvironment of the gut-associated lymphoid tissue plays a central role in orally induced nonresponsiveness by supporting the growth of regulatory T cells that maintain intestinal homeostasis in the face of constant antigenic challenge. The transfer of nonresponsiveness by peripheral T cells from antigen-fed mice suggests that these-gut-derived regulatory cells also function in peripheral sites. When oral antigens are presented with adjuvants (microbial products that activate the innate immune system) an adaptive immune response is induced to this normally tolerogenic form of antigen. This review examines recent work that has provided new insight into the regulation of tolerance and immunity in the intestinal immune system.     

Ontogeny of the immune system and the invisible frontier to immune regulation.

The data presented focus on three topics: 1) Self-reactivity of early B cells as a constitutive feature of the immune system; 2) Self-reactive V regions and their possible involvement in immune regulation; and 3) Autoantibodies directed at T cell surface molecules as a new form of direct regulation of the B cell repertoire on the T cell compartment. Evidence is provided for lack of substantial difference in the reactivity of neonatal hybridomas from normal and autoimmune mice, and the proposal is made that the immune systems of normal and autoimmune neonatal mice start with similar characteristics implying that avoidance of autoimmune disease is matter of active regulation through a process learned in ontogeny. Two general possibilities for immune regulation are discussed. One is based on the V regions of self-reactive antibodies and their antigenic determinants. The other is through natural autoantibodies able to interfere with the state of activation of T cells. It is concluded that the role of highly conserved structures like self antigens is to maintain immunoglobulin genes and favor their expression in the incipient immune system so that simple patterns of regulation can be set in motion and made available.     

Human immune system mice: current potential and limitations for translational research on human antibody responses

It has recently become possible to generate chimeric mice durably engrafted with many components of the human immune system (HIS mice). We have characterized the maturation and function of the B cell compartment of HIS mice. The antibody response of HIS mice to T cell-dependent B cell antigens is limited, and contributing factors may be the general immaturity of the B cell compartment, infrequent helper T cells selected on human MHC class II antigens, and incomplete reconstitution of secondary lymphoid organs and their microenvironments. In contrast, HIS mice generate protective antibody responses to the bacterium Borrelia hermsii, which acts as a T cell-independent antigen in mice, but do not respond to purified polysaccharide antigens (PPS). We speculate that the anti-B. hermsii response of HIS mice is derived from an abundant B cell subset that may be analogous to B1 B cells in mice. We suggest that failure of HIS mice to respond to PPS is due to the lack of a B cell subset that may originate from adult bone marrow and is highly dependent on human interleukin-7 for development.     

The immune system in the elderly

The capability to cope with infectious agents and cancer cells resides not only in adaptive immune responses against specific antigens, mediated by T and B lymphocytes clonally distributed, but also in natural immune reactions. These innate defence mechanisms include chemotaxis, phagocytosis, natural cytotoxicity, cell interactions, and soluble mediators or cytokines. However, specific and natural immune mechanisms are always closely linked and interconnected, providing the primary defense against pathogens. The Authors discuss the main changes observed with advancing age in granulocytes and natural killer (NK) cell activity, in the expression and function of adhesion molecules, and in the pattern of cytokine production. Since phagocytic function is the primary mechanism through which the immune system eliminates most extracellular pathogenic microrganisms, analysis of this function is of clinical importance. Neutrophils from aged subjects often exhibit a diminished phagocytic capacity, as well as a depressed respiratory burst, notwithstanding an activated state. The activity of NK cells during aging has been studied extensively and different results have been reported. The most consistent data indicate an increase in cells with high NK activity with advancing age. Cells from healthy centenarians can efficiently kill target cells. This finding seems to suggest that innate immunity and in particualr NK cell activity, is not heavily deteriorated with age. Conversely, a low NK activity is a predictor of impending morbidity. Immunosenescence is associated with increased expression of several cell adhesion molecules (CAM) resulting in an augmented capacity to adhere. Finally, also the cytokine network, responsible for differentiation, proliferation, and survival of lymphoid cells, undergoes complex changes with age. The main findings are a Th1 to Th2 cytokine production shift and an increased production of proinflammatory cytokines, which could explain many aspects of age-associated pathological events, such as atherosclerosis and osteoporosis.     

Restoration of the immune system with anti-retroviral therapy

Clinical benefits of highly active anti-retroviral treatments (HAART) are increasingly evidenced by resolving opportunistic infections and malignancies, as well as declining hospitalization and mortality rates [1]. This suggests that potent and sustained suppression of viral replication, at least to some extent, is associated with reconstitution of the immune system even in adult patients treated at advanced stages of the disease. Increased susceptibility to opportunistic infections and tumors mainly results from the loss of memory CD4+ T cell reactivity against recall antigens which is an early event in HIV disease progression. Primary responses of naive CD4+ T cells against new pathogens are suppressed even earlier in the course of HIV disease, and the progressive depletion in naive CD4+ T cells reflects profound alterations in T cell regeneration capacities. Previous studies revealed that monotherapy with ritonavir, a protease inhibitor, resulted in a slight improvement in memory CD4+ T cell responses to recall Ags only when detectable prior to onset of therapy, suggesting that the loss of CD4+ T cell reactivity might be irreversible at advanced stages of the disease [2]. In contrast our group demonstrated more recently that restoration in CD4+ T cell reactivity to specific antigens was feasible when HAART was administered in progressors [3]. Here we address some of the questions raised by immune restoration with HAART when administered at advanced stages of the disease.     

Systemic activation of the immune system in HIV infection: The role of the immune complexes (hypothesis)

Currently, immune activation is proven to be the basis for the HIV infection pathogenesis and a strong predictor of the disease progression. Among the causes of systemic immune activation the virus and its products, related infectious agents, pro-inflammatory cytokines, and regulatory CD4+ T cells’ decrease are considered. Recently microbial translocation (bacterial products yield into the bloodstream as a result of the gastrointestinal tract mucosal barrier integrity damage) became the most popular hypothesis. Previously, we have found an association between immune complexes present in the bloodstream of HIV infected patients and the T cell activation. On this basis, we propose a significantly modified hypothesis of immune activation in HIV infection. It is based on the immune complexes’ participation in the immunocompetent cells’ activation. Immune complexes are continuously formed in the chronic phase of the infection. Together with TLR-ligands (viral antigens, bacterial products coming from the damaged gut) present in the bloodstream they interact with macrophages. As a result macrophages are transformed into the type II activated forms. These macrophages block IL-12 production and start synthesizing IL-10. High level of this cytokine slows down the development of the full-scale Th1-response. The anti-viral reactions are shifted towards the serogenesis. Newly synthesized antibodies’ binding to viral antigens leads to continuous formation of the immune complexes capable of interacting with antigen-presenting cells.     

Antigenic cross-reactivity between human T lymphotropic virus type I (HTLV-I) and retinal antigens recognized by T cells.

To investigate the relationship between uveitis and HTLV-I infection, we examined the cross-reactivity between HTLV-I antigens and retinal antigens recognized by T cells in B10.BR mice immunized with human HTLV-I-infected MT-2 cells. We found that T cells obtained from MT-2 immune mouse spleen responded not only to HTLV-I antigens but also to retinal antigens of various species. However, they did not respond to HTLV-I-negative lymphoid cell lines. Furthermore, established T cell lines from MT-2 immune spleen cells also responded to both HTLV-I and retinal antigens. The phenotype of the immune cells that responded to both HTLV-I and retinal antigens was CD4+, CD8-, and CD3+. The proliferative response of T cell lines to HTLV-I as well as various retinal antigens, was clearly blocked by addition of anti-CD3, anti-CD4, or anti-I-Ak MoAbs, but not by anti-CD8 antibody. The established T cell lines from HTLV-I immune spleen cells were all found to be CD3+, TCR beta +, CD4+, CD8- cells by flow cytometric analysis. These results indicate that an epitope of HTLV-I antigens is cross-reactive to an epitope of retinal antigens extracted from either human retinoblastoma or normal murine, rat, and bovine retinae at a T cell recognition level.     

HLA-linked immune suppression genes

Genetic control of immune response was investigated by family and population analyses in humans. It was first recognized that there are high responders and low or non responders to natural antigens in human population. Family analysis revealed that low responsiveness to streptococcal cell wall antigen (SCW) was inherited as an HLA-linked dominant trait. CD8+ suppressor T cells existed in low responders and depletion of the CD8+ T cells from low responders could restore the strong immune response to SCW. Therefore the gene controlling the low response to SCW was designated as an immune suppression gene for SCW. Immune suppression gene for SCW was in strong linkage disequilibrium with particular alleles of HLA-DQ locus. The association between HLA-DQ alleles and low responsiveness mediated by CD8+ suppressor T cell was also observed for schistosomal antigen, Mycobacterium leprae antigen, tetanus toxoid, cryptomeria pollen antigen and hepatitis B virus surface antigen suggesting that low responsiveness to those antigens was also controlled by immune suppression genes. Anti-HLA-DR monoclonal antibodies inhibited the immune response to those antigens of high responders in vitro, but anti-HLA-DQ monoclonal antibodies did not. On the other hand, anti-HLA-DQ monoclonal antibodies restored the immune response in low responders. Therefore, it is suggested that HLA-DR upregulates immune response and that HLA-DQ downregulates it and that HLA-DQ is epistatic to HLA-DR in the regulation of immune response in humans. Furthermore, direct evidence for the differential in immune regulation between HLA-DR and DQ was obtained by analyzing the SCW specific T cell lines from low responders. SCW specific and HLA-DQ restricted CD4+ T cell lines could activate CD8+ suppressor T cells which in turn downregulate SCW specific CD4+ T cells whereas SCW specific and HLA-DR restricted CD4+ T cell lines could not activate CD8+ suppressor T cells. All these observation clearly demonstrated that the HLA-linked immune suppression genes exist in humans to control low response to natural antigens.