Enzymatic Activity of CD26 (Dipeptidylpeptidase IV) is not Required for Its Signalling Function in T Cells

Abstract CD26 is a proteolytic enzyme (dipeptidylpeptidase IV) expressed on the T cell surface that defines an alternative activation signal for human T lymphocytes. Crosslinking of CD26 via monoclonal antibodies triggers proliferation and cytotoxicity in preactivated T cells. In this study, we used highly specific competitive and irreversible inhibitors of dipeptidylpeptidase IV to study the role of the enzymatic activity in activation of CD26- transfected T cells as well as of CD26-expressing normal human T cell clones. These inhibitors at concentrations that blocked up to 95% of the enzymatic activity, did not specifically inhibit T cell activation neither via TCR/CD3 nor via CD26 itself…

A Superantigen as Virulence Factor in an Acute Bacterial Infection

This study addresses the role of a bacterial superantigen as a potential virulence factor during an acute systemic infection. BALB/c mice were intravenously infected with a recombinant Staphylococcus aureus strain capable of producing plasmid-encoded staphylococcal enterotoxin B (SEB) or with the SEB plasmid-deficient parental strain. Infection with SEB-producing bacteria resulted in an initial expansion and subsequent decrease of circulating V beta 8+ T lymphocytes. This numeric decrease was accompanied by a SEB-specific state of hyporesponsiveness of splenic T cells. In parallel with SEB-triggered unresponsiveness of a large proportion of T lymphocytes, a weakening of the overall T cell r…

Separation of T-cell-stimulating activity from streptococcal M protein

The superantigenic properties of M protein type 5 of Streptococcus pyogenes have been implicated as an important pathogenicity factor in streptococcal autoimmune diseases. Here we show that after a single purification step by affinity chromatography on immobilized albumin or fibrinogen, M protein has no mitogenic activity for T cells. We demonstrate that the superantigenicity of M proteins of type 5 and type 1 is due to contamination with the highly potent pyrogenic exotoxins of S. pyogenes in the range of 0.1 to 0.01%. These results raise a general caveat for work with these extremely active T-cell mitogens, because the mitogenicity of other streptococcal or staphylococcal proteins could b…

Diagnosis and therapy of cutaneous and mucocutaneous Leishmaniasis in Germany

The incidence of cutaneous and mucocutaneous Leishmaniasis (CL/MCL) is increasing globally, also in Germany, although the cases are imported and still low in number. The current evidence for the different therapies has many limitations due to lack of sufficient studies on the different Leishmania species with differing virulence. So far there is no international gold standard for the optimal management. The aim of the German joint working group on Leishmaniasis, formed by the societies of Tropical Medicine (DTG), Chemotherapy (PEG) and Dermatology (DDG), was to establish a guideline for the diagnosis and treatment of CL and MCL in Germany, based on evidence (Medline search yielded 400 artic…

CD2-mediated autocrine growth of herpes virus saimiri-transformed human T lymphocytes.

Herpes virus saimiri (HVS) immortalizes T lymphocytes from a variety of primates and causes acute T cell lymphomas and leukemias in nonnatural primate hosts. Here we have analyzed the requirements for growth of three HVS-transformed human T cell lines. The cells expressed the phenotype of activated T cells: two were CD4+, and one was CD8+. All three cells responded to all allogeneic human cell lines tested with enhanced proliferation, production of interleukin 2 (IL-2), and increased expression of the IL-2 receptor. Binding of CD2 to its ligand CD58 was the critical event mediating stimulation because: (a) monoclonal antibodies (mAbs) to CD2 and to CD58, but not to a variety of other surfac…

Macrophages are dispensable for superantigen-mediated stimulation and anergy induction of peripheral T cells in vivo.

Bacterial superantigens provoke T lymphocyte activation by cross-linking the variable part of the T cell receptor (TCR) beta-chain with MHC class II molecules on antigen-presenting cells. Although the molecular mechanisms of this interaction are well characterized, the in vivo accessory cell requirements for this stimulation of T lymphocytes by bacterial superantigens remain unknown. In the present study we have addressed the role of splenic macrophages in the activation of V beta 8+ peripheral T cells by staphylococcal enterotoxin B (SEB) in BALB/c mice. SEB-triggered clonal expansion and subsequent induction of unresponsiveness of both CD4+ and CD8+ T cells were investigated in naive anim…

Clonal analysis of human T cell activation by the Mycoplasma arthritidis mitogen (MAS)

Mycoplasma arthritidis produces an as yet undefined soluble molecule (MAS) that has a potent mitogenic effect on T cells of several species. We have used cloned human cytotoxic and proliferative T lymphocytes to dissect the molecular mechanism of T cell activation by this mitogen. Reactivity to MAS is clonally expressed among T cell receptor (TcR) alpha/beta chain-expressing T cell clones of CD4+ or CD8+ phenotype, as well as CD4-8- TcR alpha/beta chain-negative T lymphocyte clones expressing the CD3-associated TcR gamma chain. MAS is able to induce cytotoxicity and/or proliferation in these T cell clones. For triggering of these T cells, regardless of their phenotype of specificity, the pr…

T cells involved in psoriasis vulgaris belong to the Th1 subset

Although the pathogenesis of psoriasis vulgaris is still unknown, several characteristics point to an immunologically mediated process. Epidermal psoriatic lesions are characterized by a hyperproliferation of keratinocytes and an infiltration of T lymphocytes and granulocytes. Because the former may be mediated in part by lymphokines secreted by T cells, we have focused our interest on the in vivo and in vitro cytokine secretion patterns of T lymphocytes from psoriatic lesions. In five patients T lymphocytes were obtained from epidermal specimens. The cells were propagated with lectin and irradiated feeder cells and subsequently cloned by limiting dilution. The resulting T-cell clones were …

S1-Leitlinie Diagnostik und Therapie der kutanen und mukokutanen Leishmaniasis in Deutschland

Embryonic neural cell adhesion molecules on human natural killer cells

The neural cell adhesion molecules (NCAM) are surface glycoproteins that were first described in brain tissue. NCAM mediate adhesion in a variety of cell-cell interactions. In the present study we show that the so-called "embryonic" NCAM, i.e., the highly polysialylated forms of these proteins, are expressed on natural killer cells and some CD3+ cells in man. Homotypic binding of NCAM, believed to be of importance for cell-cell adhesion in neural tissues, appears not to be essential for NK cell-mediated killing. Yet, NCAM might be involved in NK cell migration, homing or related functions.

Stimulator cell-dependent requirement for CD2- and LFA-1-mediated adhesions in T lymphocyte activation by superantigenic toxins.

Abstract The staphylococcal enterotoxins and related microbial T cell mitogens stimulate T cells by cross-linking variable parts of the T cell receptor (TCR) with MHC class II molecules on accessory or target cells. We have used cloned human T cells and defined tumor cells as accessory cells (AC) to study the requirements for T cell activation by these toxins. On AC expressing high levels of CD54 (intercellular adhesion molecule-1, ICAM-1) and CD58 (lymphocyte function-associated antigen-3, LFA-3), mAb to CD2 were relatively ineffective in inhibiting the response to the toxins and antibodies to the lymphocyte function-associated antigen-1 (LFA-1) did not inhibit at all. If added together, h…

Concomitant loss of conformation and superantigenic activity of staphylococcal enterotoxin B deletion mutant proteins.

The T-cell-stimulating activity of staphylococcal enterotoxin B (SEB) is an important factor in the pathogenesis of certain staphylococcal diseases. To investigate the immunologically active domains of the SEB molecule, we have produced truncated fragments of recombinant SEB by C-terminal and N-terminal deletions. The fragments were expressed as fusion proteins with protein A, including a cleavage site to remove the protein A part. Mutant proteins were tested for the ability to stimulate human resting T cells and SEB-reactive T-cell clones. Deletion of only 9 amino acids from the C terminus leads to complete loss of T-cell-stimulating activity. Removing further amino acids from the SEB mole…

Evidence for T cell receptor-HLA class II molecule interaction in the response to superantigenic bacterial toxins

The staphylococcal enterotoxins and related microbial T cell mitogens stimulate T cells by cross-linking variable parts of the T cell receptor (TcR) with MHC class II molecules on accessory or target cells. In this report we describe that a given combination of T cell, accessory cell (AC) and toxin can be non-stimulatory. However, the same T cell can respond to the same toxin on another AC and the same AC can present the same toxin to another T cell. This indicates that in the complex formed between TcR, toxin and class II molecule an interaction between TcR and class II molecule takes place.

Role of bacteria-specific T cells in the immunopathogenesis of reactive arthritis.

Reactive arthritis is a usually self-limited sterile inflammation of joints that follows certain bacterial gastrointestinal or urogenital infections. The immunopathogenesis involves CD4+ T cells, which mediate an antigen-specific TH1 response to bacterial constituents within the joint. Properties of the arthritogenic bacteria and the physicochemical characteristics of the bacterial antigens may contribute to the development of reactive arthritis.

Reactivity of infiltrating T lymphocytes with microbial antigens in Crohn's disease.

Intestinal T lymphocytes are normally unresponsive to microbial and recall antigens in vitro, whereas the same antigens induce strong immune responses in peripheral-blood-derived T cells. We obtained T lymphocytes from peripheral blood and from the non-inflamed and inflamed intestinal mucosa of 6 patients (3 male, 3 female; mean age 33 years) with Crohn's disease. The T cells were stimulated in vitro with a range of microbial antigens. Whereas T cells from normal mucosa were unresponsive, those from inflamed mucosa had a proliferative response comparable to that of the peripheral-blood-derived T cells. These findings suggest that physiologic unresponsiveness to luminal antigens is abrogated…

Distribution and kinetics of superantigen-induced cytokine gene expression in mouse spleen.

The polyclonal stimulation of T cells by bacterial superantigens is involved in the pathogenesis of the toxic shock syndrome in certain staphylococcal and streptococcal infections. Here we describe the onset and kinetics of superantigen-induced cytokine production in situ in spleens of normal BALB/c mice monitored at the level of cytokine mRNA expression by in situ hybridization. Messenger RNAs for interleukin 2 (IL-2), interferon gamma, and tumor necrosis factors (TNF) alpha and beta were not expressed at detectable levels in spleens of unstimulated animals but became visible already 30 min after intraperitoneal application of 50 micrograms staphylococcal enterotoxin B. All mRNA levels sho…

The asialoglycoprotein receptor as target structure in autoimmune liver diseases.

MHC-unrestricted recognition of bacteria-infected target cells by human CD8+ cytotoxic T lymphocytes.

Abstract A CD8 + αβTCR + T cell clone (A35) was isolated from the synovial fluid of a patient with postenteric reactive arthritis caused by Yersinia enterocolitica . This clone efficiently killed autologous and allogeneic target cells that had been preincubated with live but not with heat-killed bacteria. There was no restriction by polymorphic parts of HLA-A, -B. or -C molecules and a HLA class II-deficient mutant cell line was lysed as efficiently as its normal counterpart, whereas infected HLA class I-deficient cells (Daudi cells) were not. The clone showed crossreaction between Yersinia enterocolitica , Escherichia coli , Pseudomonas aeruginosa , and Streptococcus pyogenes , but did not…

Human asialoglycoprotein receptor as an autoantigen in chronic hepatitis.

ASGPR may play a role in the pathogenesis of autoimmune chronic liver diseases. Several lines of evidence support this hypothesis. Antibodies to rabbit ASGPR could be found in various inflammatory liver diseases. In contrast, ASGPR preparations derived from human liver (h-ASGPR) were recognized predominantly by sera from patients with ai-CAH. Moreover, anti-h-ASGPR showed a close correlation to the inflammatory activity of ai-CAH both in terms of prevalence (88% in histologically proven active diseases), immunoglobulin class (IgM antibodies restricted to active inflammation) and behavior during treatment. Anti-h-ASGPR secretion could also be found in vitro, when PBL of patients were stimula…

Proliferative response of synovial fluid and peripheral blood mononuclear cells to arthritogenic and non-arthritogenic microbial antigens and to the 65-kDa mycobacterial heat-shock protein

Cellular immune responses to microbial antigens have been implicated in the pathogenesis of some forms of arthritis including reactive arthritis, Reiter's syndrome, ankylosing spondylitis and rheumatoid arthritis. We investigated the proliferative T cell responses of paired peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MC) to so-called arthritogenic bacteria (Yersinia enterocolitica and Salmonella typhimurium), to control antigens, such as Candida albicans, mumps virus and purified protein derivative, to the recombinant mycobacterial 65-kDa heat-shock protein (hsp 65) and the mitogen phytohemagglutinin (PHA) in 16 patients with different inflammatory rheumatic diseases. T…

Phosphodiesterase inhibitor pentoxifylline, a selective suppressor of T helper type 1- but not type 2-associated lymphokine production, prevents induction of experimental autoimmune encephalomyelitis in Lewis rats

The phosphodiesterase inhibitor pentoxifylline (POX), which is known to have pharmacological effects in animal models of multiorgan failure and endotoxin-mediated shock, was tested for its immunosuppressive potential on T lymphocyte activation in vitro and in vivo. POX was found to have a profound inhibitory effect on both mitogen- and antigen-induced proliferation of CD4+ T cells in vitro. This inhibitory activity of the drug could be reproduced by treating T lymphocytes with cAMP analogues during stimulation. Responses of repeatedly in vitro stimulated cells were much more strongly inhibited by the drug and by cAMP analogues than responses of fresh resting lymphocytes. Furthermore, POX co…

Multiclonal Synovial T Cell Response toYersinia enterocoliticain Reactive Arthritis: TheYersinia61-kDa Heat-Shock Protein Is Not the Major Target Antigen

The T cell response to bacterial antigens plays a major role in the pathogenesis of reactive arthritis (ReA) following enteric infections with Yersinia enterocolitica. To study the antigen specificity of the T cells at the site of inflammation, the response of cloned T cells from the synovial fluid of 2 patients with ReA to partially purified antigens of Yersinia enterocolitica was determined. The clones showed different patterns of response to various fractions, indicating a multiclonal response to Yersinia antigens, and these specificities differed in the 2 patients. Some T cells were specific for Y. enterocolitica; some cross-reacted with other enterobacteria. Proteins of 14 and 19 kDa c…

Herpes virus saimiri-transformed human T lymphocytes: normal functional phenotype and preserved T cell receptor signalling

Herpes virus saimiri (HVS), a primate herpes virus, transforms human CD4+ and CD8+ T lymphocytes to continuous growth in vitro. We have previously shown that HVS-transformed human T cells (HVS-T cells) respond to stimulation via CD2 with autocrine growth. In the present study we have investigated the functional characteristics of HVS-T cells. We describe that these cells can perform all the functions of normal T cells, i.e. cytokine secretion, cytotoxicity, and exocytosis of granule esterases. All these activities can be triggered via CD2 by binding to its natural ligand or via the TCR, e.g. by anti-TCR antibodies, by recognition of a bacterial superantigen and by MHC-restricted recognition…

Protection from experimental allergic encephalomyelitis by application of a bacterial superantigen

Certain bacterial and viral T cell stimulating proteins ('superantigens') are known to be very potent activators of T cells with certain V beta receptors. When applied in vivo these molecules induce anergy in those T cells responding to them. In this study we have investigated the influence of staphylococcal enterotoxins (SE) on myelin basic protein (MBP)-specific T cells in Lewis rats. As MBP-specific T cells in rats belong exclusively to the V beta 8.2+ CD4+ subset, the induction of experimental allergic encephalomyelitis (EAE) allows for an estimation of the functional state of the respective V beta-bearing T cells after enterotoxin-induced activation. In vitro, various MBP-specific T ce…

Stimulation of human T cells by microbial 'superantigens'.

The enterotoxins and the TSST of S. aureus, the erythrogenic toxins A and C of S. pyogenes and a still uncharacterized exoprotein of M. arthritidis belong to a family of exotoxins that have in common a potent mitogenic activity for T lymphocytes of several species. These proteins stimulate CD4+ and C8+ T cells, as well as a fraction of gamma delta TCR-bearing T cells by cross-linking variable parts of the T cell antigen receptor with MHC class II molecules on accessory or target cells. They are functionally bivalent molecules having distinct interaction sites for variable parts of the TCR and for nonpolymorphic parts of the MHC class II molecule. For alpha beta TCR-bearing T cells the V bet…

T cell activation defect in hemodialysis patients: Evidence for a role of the B7/CD28 pathway

T cell activation defect in hemodialysis patients: Evidence for a role of the B7/CD28 pathway. The immunosuppressive effect of chronic renal failure is correlated with an impaired proliferation of peripheral blood leukocytes in vitro . This is mainly due to an impaired function of the accessory cells rather than the T cells. Here we tried to define a missing accessory signal for T cell activation in hemodialysis patients. We substituted cell surface bound molecules by adding tumor cell lines to the in vitro assays that express different patterns of accessory molecules. Cell lines that express the costimulatory B7 molecule reconstituted the activation of patients' cells whereas B7 negative c…

Salmonella-reactive Synovial Fluid T-cell Clones in a Patient with Post-infectious Salmonella Arthritis

From a patient with reactive arthritis following Salmonella typhimurium enteritis, synovial fluid T-lymphocytes were cloned and expanded in vitro. Seven out of 74 clones showed a marked proliferative response to antigens of heat-killed Salmonella typhimurium with autologous T-cell-depleted peripheral blood mononuclear cells as antigen-presenting cells. The Salmonella-reactive clones were of the CD4+ phenotype, antigen-induced proliferation could be inhibited by a monoclonal antibody to HLA class II. One clone recognized both Salmonella and Campylobacter jejuni antigens in the proliferation assay. The multiclonality of Salmonella-reactive synovial fluid T-cells indicates that the microorgani…

T lymphocyte-stimulating microbial toxins as ?superantigens?

Infectious pathogens generally have to cope with the host's adaptive immune system, i.e., T and B lymphocytes. Common evasion mechanisms in this complex interaction are antigenic variations, the escape to immunologically priviledged sites or the use of immunosuppressive mechanisms. Many bacteria and other microorganisms eleborate soluble factors or toxins that act suppressively on cells of the immune system, such as pore-forming molecules or proteins that interfere with the function of G proteins. Gram-positive cocci and a mycoplasma have developed an extremely potent mechanism of T cell stimulation by closely mimicking recognition of specific antigen. From the functional similarity to anti…

Interleukin-6 production in "normal" and HTLV-1 tax-expressing brain-specific endothelial cells.

Abnormal cytokine production can contribute in many instances to the development of pathology. Our study focuses on the regulation of interleukin (IL)-6 production in vitro in brain-specific endothelial cells (BEC) under physiological conditions and in a model of human T leukemia virus-1 (HTLV-1) infection. IL-6 production was strongly up-regulated in a dose-dependent mode upon exposure to recombinant IL-1 beta, although nearly not detectable in unstimulated BEC. This induction of IL-6 production could be achieved by reagents known to increase intracellular levels of cAMP, such as forskolin, prostaglandin E or pentoxifylline. Furthermore, transcription and production of IL-6 was inducible b…

Synovial fluid-derivedYersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells

Humoral and cellular immune reactions to heat-shock proteins have been implicated in the pathogenesis of arthritis. Heat-shock proteins occur in bacteria as well as all eukaryotes and have been highly conserved during evolution. Cross-reactivity between bacterial and human heat-shock proteins induced at the site of inflammation may underlie the pathogenesis of some forms of arthritis. In order to test this hypothesis, we raised and cloned a Yersinia-specific T cell line from the synovial fluid lymphocytes of a patient with Yersinia-induced reactive arthritis. From this line we obtained a CD4+ T cell clone that proliferated in response to Yersinia antigens and both to the mycobacterial and t…

Function of Dipeptidyl Peptidase IV (CD26, Tp103) in Transfected Human T Cells

CD26 (Tp103) is a proteolytic enzyme (dipeptidyl peptidase IV) expressed on the T cell surface that defines an alternative activation signal for human T lymphocytes. It is absent from or present in only low amounts on resting T cells but it is expressed strongly after activation. Crosslinking of CD26/Tp103 via the monoclonal antibody CB.1 triggers functional activities in preactivated T cells. To study the molecular requirements for T cell activation via CD26 we transfected a cDNA encoding CD26 into several CD26-negative cells. In Jurkat T cell leukemia cells that normally do not express the CD26 antigen, the transfected CD26 molecule is functional because the monoclonal antibody CB.1 induc…

Major histocompatibility complex class II binding site for streptococcal pyrogenic (erythrogenic) toxin A.

Streptococcal pyrogenic exotoxin A (SPEA) is an important pathogenicity factor of group A streptococci. It is a member of the family of „superantigens” produced by Staphylococcus aureus and Streptococcus pyogenes and its T lymphocyte stimulating activity is involved into the pathogenesis of certain diseases caused by pyogenic streptococci. In this study we have produced and characterized recombinant SPEA molecules in Escherichia coli. These molecules are indistinguishable from natural SPEA in both T cell stimulatory and HLA class II binding activities. Human class II molecules are more efficient than mouse class II molecules in presenting SPEA to T cells. In binding tests to major histocomp…

Mutations affecting MHC class II binding of the superantigen streptococcal erythrogenic toxin A.

Streptococcal pyrogenic exotoxin A (SPEA) is an important pathogenicity factor of group A streptococci. It is a member of the family of 'superantigens' produced by Staphylococcus aureus and Streptococcus pyogenes, and its T lymphocyte stimulating activity is involved in the pathogenesis of certain diseases caused by pyogenic streptococci. In this study we have generated nine mutant SPEA molecules by substituting amino acids in the regions of homology between different streptococcal and staphylococcal superantigens. An additional mutant was created by deletion of the 10 N-terminal amino acids. The mutants were expressed as fusion proteins. Several mutations led to a loss of function due to a…

The human hepatic asialoglycoprotein receptor is a target antigen for liver-infiltrating T cells in autoimmune chronic active hepatitis and primary biliary cirrhosis.

Autoantibodies to the human hepatic asialoglycoprotein receptor have been found in nearly 50% of the sera of patients with autoimmune chronic active hepatitis and in 15% of patients with primary biliary cirrhosis. In this study we demonstrate that the human hepatic asialoglycoprotein receptor is also a target antigen for T cell-mediated immune responses. Peripheral blood lymphocytes of 37% (7 of 19) of patients with autoimmune chronic active hepatitis and 33% (2 of 6) of patients with primary biliary cirrhosis showed a proliferative response to highly purified human hepatic asialoglycoprotein receptor, whereas no proliferation was found with peripheral blood lymphocytes of patients with chr…

Production of interleukin-6, tumor necrosis factor α and interleukin-10 in vitro correlates with the clinical immune defect in chronic hemodialysis patients

Production of interleukin-6, tumor necrosis factor α and interleukin-10 in vitro correlates with the clinical immune defect in chronic hemodialysis patients. In patients with chronic renal failure alterations in monokine production are a common feature. Their clinical relevance has not yet been proven. We show here a correlation between an overproduction of interleukin-(IL)-6 and tumor necrosis factor alpha (TNFα) upon stimulation with LPS by mononuclear cells in vitro and the clinical grade of immunodeficiency found in these patients. Higher levels of IL-6 and TNFα were correlated with an immunocompromized state, that is, non-responsiveness to hepatitis B vaccination, whereas patients with…

Predominance of Th1-type T cells in synovial fluid of patients with Yersinia-induced reactive arthritis

The pathogenetic mechanisms underlying the development of reactive arthritis and the functional capacities of synovial T cells specific for Yersinia enterocolitica are still unclear. In this study we have determined the cytokine secretion patterns of 24 CD4+ synovial fluid (SF)-derived T cell clones from 2 patients with Yersinia-induced reactive arthritis, 16 clones specific for different Yersinia antigens and 8 clones as controls. The clones specific for Yersinia antigens predominantly belong to the T helper cell 1 (Th1) subset with production of interferon (IFN)-gamma and interleukin (IL)-2, but no IL-4, whereas SF T cells not reactive with Yersinia antigens produce IL-2, IL-4 and IFN-gam…

Recombinant epidermolytic (exfoliative) toxin A of Staphylococcus aureus is not a superantigen

The epidermolytic (exfoliative) toxins produced by Staphylococcus aureus cause epidermolysis and skin blistering. In addition, they have been implicated to belong to the group of T lymphocyte stimulating molecules known as "superantigens". Here we show that recombinant epidermolytic toxin A produced in S. aureus is not mitogenic for human and murine T lymphocytes. We discuss the possibility that minute contaminations of highly mitogenic exoproteins may cause the mitogenicity in several proteins that are reported to be superantigens.

Differential expression of mRNA encoding interleukin-12 p35 and p40 subunitsin situ

Interleukin-12 (IL-12) is a heterodimeric cytokine that plays an important role in the regulation of the immune response. For biological activity the expression of both subunits of IL-12, p35 and p40, is required. Moreover, in the mouse the p40 chain of IL-12 specifically inhibits the effects of the IL-12 heterodimer. In the present study we have analyzed by in situ hybridization the expression of the p35 and p40 mRNA in the spleens of BALB/c and mutant (SCID, nude, beige) mice, unstimulated and after in vivo stimulation with lipopolysaccharide (LPS) and with staphylococcal enterotoxin B (SEB). In unstimulated spleens of BALB/c mice p35 and p40 mRNA were only detectable in a few strongly st…