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Investigation of the nature of the increased erythrocyte-antibody (EA) binding activity of peripheral blood lymphocytes (PHL) from rheumatoid arthritis (RA) patients reported in the preceding paper has revealed that IgG is the active class of antibody in this rosette formation. Some IgM binding also occurs. SRBC sensitized with F(ab)2 preparations of IgG do not give rosette formation even at high concentrations. EA binding is inhibited by prior incubation of lymphocytes with heat-aggregated human IgG but antigen-antibody complexes did not give significant inhibition. The majority of these rosettes were found to be stable at 4°C. and room temperature but labile at 37°C. Enzyme studies with pronase, trypsin, neuraminidase and treatment with sodium azide gave results strongly supporting the conclusion that the increased binding observed is increased Fc-receptor activity. This activity appears not to be a result of Fc binding by cell-bound rheumatoid factor. A range of titres of antibody and of IgG was used to sensitize erythroeytes to form EA and the enhanced EA-rosette formation by PBI, from RA patients occurred throughout the range of concentrations of sensitizing antibody. Significantly more EA were bound by individual lymphocytes from RA patients than control subjects. This data suggest that the Fc receptors on RA lymphocytes are more avid for FA than receptors on lymphocytes from healthy people. [ABSTRACT FROM AUTHOR]

The mononuclear cells from. the joint fluid of certain patients with inflammatory arthritis are shown to be more cytotoxic to a polyploid strain of homologous liver cells than were equivalent numbers of peripheral blood lymphocytes From the same donors. The diagnostic categories of these patients are essentially similar to those of a group of patients studied by Hedberg (1967) in whom joint fluid mononuclear cells were cytotoxic to monolayers of human foetal fibroblasts. Evidence is presented to show that this cytotoxic activity is attributable to lymphocytes, as opposed to polymorphonuclear leucocytes or phagocytic mononuclear cells which adhere to glass. It is not excluded that the latter population may also have some cytotoxic potential. It is argued that the target cell damage described in this paper is probably not induced by any antigen on the target cell. The implications of this suggestion are discussed in relation to the pathogenesis of inflammatory joint disease. [ABSTRACT FROM AUTHOR]

The article presents a notice of redundant publication on topics related to clinical and experimental immunology. The text and data of the paper "Peptide immunization in humans: a combined CD8+ T cell-targeted vaccine restimulates the memory CD4 T cell response but fails to induce cytoxic T lymphocytes (CTL)" is replicated without acknowledgement in the subsequent paper. The data indicate that the CTL peptide failed to stimulate a cytotoxic immune response.

Previous studies have shown the down-regulating in vitro effect of cocoa flavonoids on lymphocyte and macrophage activation. In the present paper, we report the capacity of a long-term rich cocoa diet to modulate macrophage cytokine secretion and lymphocyte function in young rats. Weaned rats received natural cocoa (4% or 10% food intake), containing 32 mg flavonoids/g, for 3 weeks. Spleen immune function was then evaluated through the analysis of lymphocyte composition, their proliferative response and their ability to secrete cytokines and Ig. In addition, the status of activated peritoneal macrophages was established through tumour necrosis factor (TNF)-α secretion. The richest cocoa diet (10%) caused a reduction of TNF-α secretion by peritoneal macrophages showing anti-inflammatory activity. Similarly, although a 10% cocoa diet increased lymphocyte proliferation rate, it down-regulated T helper 2 (Th2)-related cytokines and decreased Ig secretion. These changes were accompanied by an increase in spleen B cell proportion and a decrease in Th cell percentage. In summary, these results demonstrate the functional activity of a cocoa-high dosage in down-regulating the immune response that might be beneficial in hypersensitivity and autoimmunity. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is characterized by an excessive inflammatory response to inhaled particles, mainly tobacco smoking. T lymphocytes are important regulatory cells that secrete several cytokines and participate actively in this inflammatory response. According to the pattern of cytokines secreted, the immune response is classified as cytotoxic or type 1 [interferon (IFN)-γ-, interleukin (IL)-2-dependent] and humoral or type 2 (IL-4-, IL-5-, IL-10- and IL-13-dependent). This paper sought to compare the intracellular profile of cytokine expression determined by flow cytometry in T lymphocytes harvested from bronchoalveolar lavage (BAL) and peripheral blood in patients with COPD, smokers with normal lung function and never smokers. We found that BAL T lymphocytes from COPD patients had a higher percentage of positive stained cells for most of the cytokines analysed when compared to never smokers or smokers with normal lung function. Differences reached statistical significance for IL-4, IL-10 and IL-13, particularly in CD8+ T cells. Furthermore, the expression of most of these cytokines was related inversely to the degree of airflow obstruction present suggesting local activation and/or selective homing of T lymphocytes to the lungs in COPD patients. These observations were not reproduced in circulating T lymphocytes. These results suggest that BAL T lymphocytes in patients with COPD produce more cytokines than in controls and tend to show a type 2 pattern of intracellular cytokine expression, particularly a Tc-2 profile. This is related inversely to the degree of airflow obstruction present. [ABSTRACT FROM AUTHOR]

An increasing number of cell types, including peripheral blood mononuclear cells (PBMCs), have been demonstrated to release heat shock proteins (Hsps). In this paper we investigate further the hypothesis that Hsps are danger signals. PBMCs and Jurkat cells released Hsp70 (0·22 and 0·7 ng/106 cells, respectively) into medium over 24 h at 37°C. Release of Hsp70 was stimulated 10-fold by GroEL ( P < 0·001) and more than threefold by lipopolysaccharide (LPS) ( P < 0·001). Although Hsp60 could be detected in the medium of cells cultured at 37°C for 24 h, the low rates of release were due probably to cell damage. Significant release of Hsp60 was observed when Jurkat cells were exposed to GroEL (2·88 ng/106 cells) or LPS (1·40 ng/106 cells). The data are consistent with the hypothesis that Hsp70 and Hsp60 are part of a danger signalling cascade in response to bacterial infection. [ABSTRACT FROM AUTHOR]

Protection against tuberculosis depends upon the generation of CD4+ T cell effectors capable of producing IFN-γ and stimulating macrophage antimycobacterial function. Effector CD4+ T cells are known to express CD44hiCD62Llo surface phenotype. In this paper we demonstrate that a population of CD44hiCD62Llo CD4+ effectors generated in response toMycobacterium bovisBCG orM. tuberculosisinfection in C57BL/6 mice is heterogeneous and consists of CD27hi and CD27lo T cell subsets. These subsets exhibit a similar degree ofin vivoproliferation, but differ by the capacity for IFN-γ production.Ex vivoisolated CD27lo T cells express higher amounts of IFN-γ RNA and contain higher frequencies of IFN-γ producers compared to CD27hi subset, as shown by real-time PCR, intracellular staining for IFN-γ and ELISPOT assays. In addition, CD27lo CD4+ T cells uniformly express CD44hiCD62Llo phenotype. We propose that CD27lo CD44hiCD62Llo CD4+ T cells represent highly differentiated effector cells with a high capacity for IFN-γ secretion and antimycobacterial protection at the site of infection. [ABSTRACT FROM AUTHOR]

Activation of T cells requires both TCR-specific ligation and costimulation through accessory molecules during T cell priming. IFNγ is a key cytokine responsible for macrophage activation duringMycobacterium tuberculosis(Mtb) infection while IL-10 is associated with suppression of cell mediated immunity in intracellular infection. In this paper we evaluated the role of IFNγ and IL-10 on the function of cytotoxic T cells (CTL) and on the modulation of costimulatory molecules in healthy controls and patients with active tuberculosis (TB).γ-irradiated-Mtb(i-Mtb) induced IL-10 production from CD14+ cells from TB patients. Moreover, CD3+ T cells of patients with advanced disease also produced IL-10 after i-Mtbstimulation. In healthy donors, IL-10 decreased the lytic activity of CD4+ and CD8+ T cells whereas it increasedγδ-mediated cytotoxicity. Furthermore, we found that the presence of IL-10 induced a loss of the alternative processing pathways of antigen presentation along with a down-regulation of the expression of costimulatory molecule expression on monocytes and macrophages from healthy individuals. Conversely, neutralization of endogenous IL-10 or addition of IFNγ to either effector or target cells from TB patients induced a strong lytic activity mediated by CD8+ CTL together with an up-regulation of CD54 and CD86 expression on target cells. Moreover, we observed that macrophages from TB patients could use alternative pathways for i-Mtbpresentation. Taken together, our results demonstrate that the presence of IL-10 duringMtbinfection might contribute to mycobacteria persistence inside host macrophages through a mechanism that involved inhibition of MHC-restricted cytotoxicity against infected macrophages. [ABSTRACT FROM AUTHOR]

In this paper we review different aspects of B cell development on the path from the proB cell to the memory B cell and the plasmocyte. Emphasis is given to the positive and negative selection effects mediated by the changing forms of the surface immunoglobulin (Ig) receptor under successive microenvironments. Positive selection is linked to λ chain expression at the pro- and preB cell slage in fetal liver and bone marrow. Negative selection takes place when surface (s)IgM is being cross- linked by autoantigens before the immature B cell can leave, or after it has left, the bone marrow. After somatic mutation, major expansion becomes possible for B cells with high-affinity sIg receptors. This takes place in the germinal centres of the secondary lymphoid organs in the context of major histocompatibility complex (MHC) restriction and provided the necessary T cell help is given. Kinetic data on B cell replenishment in the rodent models are used to draw a schematic view of an established B cell repertoire. [ABSTRACT FROM AUTHOR]

IL-6, an important mediator of the acute phase response, has been implicated in the pathogenesis of rheumatoid arthritis (RA). Many cell types including macrophages, T cells. H cells, endothelial cells and fibroblasts can produce this cytokine and production is largely regulated at the level of gene transcription or mRNA stabilization. In this paper we have first measured the levels of IL-6 activity in synovial fluid (SF) and serum from patients with RA and then localized IL-6-producing cells in the synovium by in situ hybridization combined with immunophenotyping. Patients with RA had raised levels of IL-6 in both SF and serum compared with patients with osteoarthritis and age-matched healthy controls. in individual RA patients tested serially after admission to hospital, serum IL6 was initially raised and, unexpectedly. increased with clinical improvement, in situ hybridization of IL-6 mRNA showed positive cells both in the lymphocyte-rich aggregates and adjacent to small blood vessels. With immunophenotyping it was found that cells containing IL-6 mRNA were often in contact with CD 14+ tissue macrophages and double immunophenotyping revealed that immuno- reactive IL-6 was often associated with synovial T cells. [ABSTRACT FROM AUTHOR]

This paper describes the spontaneous occurrence of an autoimmune uveoretinitis in nude (nu/nu) mice reconstituted when 4 weeks old by the grafting of rat embryonic thymus. The uveoretinitis was characterized histologically by progressive loss of the photoreceptor layer, observed in 4.0, 17.6, 42.9% and 71.4% of such mice at 3, 5, 7 and 12 months of age, respectively. Mice with uveoretinitis were shown to have serum IgG antibody reactive by indirect immunofluorescence with retinal photoreceptors, and with interphotoreceptor retinoid-binding protein (IRBP), but not retinal S-antigen, by immunoblotting and ELISA. A uveoretinitis could be adoptively transferred to syngeneic ungrafted nude mice by splenic CD4+ T cells from diseased animals. This is the first experimental model of a (T cell mediated) autoimmune uveoretinitis which develops spontaneously and which is not dependent upon deliberate sensitization with retinal antigens and adjuvants. [ABSTRACT FROM AUTHOR]

Humoral and cell-mediated responses to crude and purified parasite antigens were examined in patients with active cutaneous leishmaniasis caused by Leishmania major. The patients had serum antibody titres against parasite lysates ranging from 1/500 to 1/10 000 and recognized multiple components by Western blotting with molecular weights between 5000 and > 200 000. Several components, particularly at 5 and 50 kD, were recognized by most of the patients. The lymphoproliferative responses to two pure antigens, promastigote surface protease and lipophosphoglycan, both considered potential candidates for the development of a human vaccine were measured. No response to promastigote surface protease was observed even at 10 μg/ml; however, weak proliferation to lipophosphoglycan was consistently present. T cell blots examining peripheral blood lymphocyte proliferation, showed antigen-specific responses to a 72-82 kD component in promastigote lysates. [ABSTRACT FROM AUTHOR]

The binding of EPF to lymphocytes stimulates the release of soluble mediators, active in T cell dependent reactions, namely the rosette inhibition test and the adoptive transfer of contact sensitivity. On the basis of their ability to inhibit the delayed type hypersensitivity reaction in this latter assay, they have been classified as suppressor factors. This paper describes the identification of two EPF-induced suppressor factors. Unlike EPF which is neither species-restricted nor strain-restricted, these factors are genetically restricted in their action in the rosette inhibition test EPF-S1 (estimated Mr 14,000) is restricted to the I region of the mouse MHC, while EPF-S2 (estimated Mr 55,000) is restricted to a locus (or loci) outside the MHC. Like other antigen non-specific factors, release of these suppressor factors can be stimulated also by Con A. [ABSTRACT FROM AUTHOR]

Freshly isolated B cells from chronic lymphocytic leukaemia patients (B-CLL) have been previously shown to induce a strong proliferative response and high levels of NK-like activity in lymphocytes from healthy donors. The present paper deals with the origin, mitotic state, target spectrum and cell surface phenotype of the NK-like effectors generated after stimulation with B-CLL. Experiments using large granular lymphocytes (LGL) and T cells as responders demonstrated that most of the precursors of the newly generated NK-like effectors express the CD3 antigen. The induction of NK-like activity paralleled cell activation, as judged by blast transformation, thymidine uptake and appearance of cell surface activation markers. The newly generated NK-like effectors displayed a T cell phenotype and a broader target repertoire than native NK cells. [ABSTRACT FROM AUTHOR]

This paper reports a study of the locomotor behaviour of the lymphocytes from 17 patients with chronic lymphocytic lcukaemia (CLL). The cells were studied both immediately after separation from blood and after culture for 24 to 48 h with a range of growth activators. Cells direct from blood were tested for polarization in fetal calf serum (FCS 20%), phorbol myristate acetate (PMA 10-7 M) and colchicine (10-5 M). The polarization of lymphocytes from CLL patients with high white cell (WBC) counts (> 10 × 109/litre) was very poor in FCS and PMA. though the cells from about half of these patients responded well to colchicine. The response of cells from patients with low white cell counts was the same as that of controls. The growth activators, PHA (1 /Lg/ml), anti-CD3 antibody (OKT3 25 ng/ml). Cowan strain Staphylococcus aureus (SAC: 15 × 107/ml) and PMA (10-8 M) induced an increase in the proportion of locomotor lymphocytes from controls and from CLL patients with low white cell counts during 4 h of culture. Cells from patients with high white cell counts showed very little increase in locomotor forms in any activator including PMA and the B cell mitogen SAC. This detect was seen in both polarization assays and collagen gel invasion assays. The findings suggest that CLL lymphocytes have a defect of locomotion demonstrable at two levels: (a) the cells fail to respond by polarizing immediately upon stimulation; colchicine treatment reverses this defect in some cases: (b) they also fail to acquire locomotor capacity during culture with activators of growth. [ABSTRACT FROM AUTHOR]

Corticosteroids have been reported to stimulate immunoglobulin (Ig) production by otherwise unstimulated peripheral blood mononuclear cells. In this paper we confirm that observation but report the necessity for an additional minor antigenic stimulus. Lymphocytes cultured with HB101, a complete medium not requiring serum supplement, did not increase Ig production after addition of hydrocortisone, but did if small concentrations (1-10%) of fetal calf serum were added. Various antigens such as Candida, tetanus, and albumin of different sources could substitute for fetal calf sera in allowing corticosteroids to stimulate Ig production in resting lymphocytes. We conclude that corticosteroids do not stimulate Ig production by lymphocytes de novo, rather, corticosteroids greatly enhance the Ig production stimulated by the foreign antigens present in fetal calf sera. [ABSTRACT FROM AUTHOR]

IL-2 receptor expression by B cells has previously been considered to be confined to activated normal B cells and, among the B cell leukaemias, to the hairy cells (HC) of hairy-cell leukaemia. In the present paper, using α-Tac monoclonal antibodies in a highly sensitive indirect rosette method, we show that both normal and certain leukaemic B cells other than HC express IL-2 receptors. The density of these receptors is low since they were not detectable by indirect immunofluorescence. Various controls excluded non-specific-reagent or exogenous receptor binding and blocking studies with recombinant IL-2 confirmed the presence of the IL-2 receptors. The significance of the findings is discussed and it is suggested that B cell IL-2 receptor expression without in-vitro activation may be a function of B cell maturity. [ABSTRACT FROM AUTHOR]

It has been shown that sera from chagasic patients with positive EVI serology could act in co-operation with complement or normal human lymphocytes as a partial β-adrenoceptor agonist increasing the contractile tension and frequency of isolated rat atria, as occurs with IgG purified from chagasic serum. In this paper we demonstrate that IgG present in chagasic patients sera could bind to the β-adrenoceptors of the heart and stimulate contractile activity of myocardium. The positive inotropic and chronotropic effect could be blocked by the specific β1-adrenoceptor antagonist but not by the β2-adrenoceptor antagonist. Chagasic IgG inhibited the binding of (-) ⊃3H-DHA to β-adrenoceptors of purified rat myocardial membranes behaving as non-competitive inhibitors. The reactivity of chagasic serum or IgG with β1-adrenoceptor was lost after absorptions with turkey red blood cells. In contrast, guinea-pig red blood cells were unable lo remove the β1 reactivity of chagasic serum or chagasic IgG. This supports the specificity of β1-adrenoceptors of the chagasic IgG and the independence of β1-adrenoceptor reactivity in relation to the EVI system. Clinical specificity of the β1-adrenoceptor reactivity seems rather high in Chagas' disease since it was lacking in 14 individuals with other cardiopathies, such as ischaemic and rheumatic heart disease, even after heart surgery. [ABSTRACT FROM AUTHOR]

The antigen-induced DNA synthesis in vitro in lymphocytes from patients with acute Plasmodium falciparum malaria was investigated. The patients and healthy controls from Sweden or Colombia were the same as those studied in the accompanying paper (Troye-Blomberg el al., 1983). The malarial antigens used were sonicated membrane preparations or purified and concentrated supernatants from in vitro cultures of P. facliparum, similar preparations derived from normal human erythrocytes served as control antigen. In the patients' lymphocytes P. falciparum antigens induced a weak or moderate but significant stimulation of DNA synthesis, peaking after 3-4 days of incubation. This early response was specific for P. faleiparum since it was not obtained with lymphocytes from healthy donors nor with those from patients with acute P. vivax or P. ovale malaria. No antigen-induced response was seen in about half of the P.falciparum patients. However in a few negative eases, available for consecutive testing, positive reactions were seen with lymphocytes taken 2 weeks after infection when the blood of these patients was free of parasites. The early response induced in patients' lymphocytes to the P. falciparum antigens was not obtained with RBC antigen, however, these preparations frequently induced a response rising to significant levels later during incubation (day 5-6)- Similar delayed responses were obtained when either- patients' or control donors' lymphocytes were exposed to the P. falciparum antigens. This indicates that both the RBC and the parasite preparations contained mitogenic substances affecting human lymphocytes in general and easily obscuring the P, falciparum specific responses seen only in the patients. This latter response was relatively low and short lived, suggesting that it reflected a secondary in vitro stimulation of in vivo primed lymphocytes and that it was regulated by suppressor mechanisms. [ABSTRACT FROM AUTHOR]

Motor end-plate disease (Med) in mice is associated with complex immunological abnormalities which are shared by the heterozygous + /MedJ mice, which exhibit no or mild clinical manifestations, and by MedJ/MedJ mice which die from this neuromuscular disorder. In the present paper we extend our immunological data with the study of splenic lymphocyte subsets with Lyt monoclonal antibodies. Both MedJ/ MedJ and +/MedJ 14-18 day old mice have high Lytl&plus;/Lyt2&plus ratios, with higher Lytl &plus; and reduced Lyt2&plus; lymphocyte pools as compared to normal mice. This correlates with the low suppressive function previously described, but is unexpected in view of the low helper function as measured by the response to SRBC immunization. Adult +/MedJ mice recovered normal T lymphocyte subset levels, while the small group of MedJ/MedJ mice that escapes death but continues to suffer from the neuromuscular illness maintains high Lyti&plus;/Lyt2&plus; ratios. [ABSTRACT FROM AUTHOR]

The initiation of cytoplasmic Ig synthesis in differentiating B cells is accompanied by the start of cytoplasmic J chain production. As the cell matures further. J chain synthesis ceases (unless it is producing dimeric IgA or 19S IgM). In consequence, it is common to find Ig-positive, J chain-negative cells in reactive lymphoid tissue. However, the reverse pattern (Ig-negative! J chain-positive), which would indicate J chain production unaccompanied by Ig synthesis, has not been reported. In this paper we describe the detection of such cells in reactive human lymphoid tissue by a double immunoenzymatic labelling technique. Furthermore, retrospective immunohistological analysis of 90 cases of human high-grade lymphoma revealed three cases in which the neoplastic cells appeared to synthesize J chain but not Ig. These findings suggest that the term J chain disease might be introduced to describe this new class of lymphoid neoplasm. However, it is pointed out that immunochemical categories of human B lymphoproliferative diseases based upon patterns of Ig synthesis are often in direct conflict with histological categories (cf. mu chain-producing neoplasms) and the term J chain disease cannot therefore be recommended. It is probable that further cases of J chain-positive, Ig-negative lymphoid neoplasms, covering a range of histological categories, will be described in the future. [ABSTRACT FROM AUTHOR]

Peripheral blood lymphocytes from 105 subjects with different forms of leprosy and healthy contacts of leprosy patients were stimulated in vitro with different preparations of mycobacterial antigens alone or in combination with a suboptimal dose of phytohaemagglutinin (PHA). In nearly all individuals sonicated leprosy bacilli and PHA together gave a lower 3H-thymidine incorporation than did the same dose of PHA alone. There was no difference in the degree of inhibition seen in the different patient groups or the healthy contacts. High doses of whole, washed Mycobacterium leprae, combined with PHA led to an increased thymidine incorporation in borderline tuberculoid leprosy patients who had experienced a reversal reaction, and in healthy contacts with more than 6 months of exposure, while most lepromatous patients and contacts with less than 6 months exposure did not show an augmentation of the PHA-induced thymidine incorporation. The inhibition exerted by sonicated M. leprae was dose-dependent, seen even with very low doses of antigen, and was not due to direct cytotoxicity. M. bovis, strain BCG, was weakly suppressive in combination with PHA, and sonicated M. duvalii had a very marked suppressive effect. There was no correlation between the suppressive effect of M. leprue antigens and the other mycobacteria neither was there any correlation with the responses to the mycobacterial antigens alone. Many lepromatous leprosy patients showed significant suppression of background incorporation with addition of M. leprae antigens. This paper discusses whether the apparent `non-responsiveness' in lepromatous leprosy could be due to active suppressor mechanisms operative in vivo. [ABSTRACT FROM AUTHOR]

Lymphocytes bearing complement receptors were separated from lymphocyte suspensions using C3-reacted Sepharose columns as solid phase immunoabsorbents. The retained CR + lymphocytes were recovered by elution of the column with IgG fraction purified from a rabbit antiserum to human C3. This paper describes the method, its specificity and the yields of cells obtained. [ABSTRACT FROM AUTHOR]

This paper describes experiments in which human peripheral blood lymphocyte trans- formation by phytohaemagglutinin (PHA) is augmented by the addition of human dialysable transfer factor. Dextran-separated peripheral blood leucocytes were cultured for 4 days with a range of PHA concentrations so as to produce low, moderate, high or very high incorporation of [³H]thymidine. When transfer factor preparations were added to the cultures, in concentrations similar to those augmenting lymphocyte transformation to tuberculin PPD, augmentation of PHA responses was observed in two-thirds of the experiments (25/38). In these experiments the extent of augmentation was proportional to the level of DNA synthesis induced by PHA in the absence of added transfer factor. It appears that preparations of transfer factor are able to augment lymphocyte transformation responses to PHA in vitro, but that this effect occurs with less regularity than does augmentation of lymphocyte transformation to tuberculin PPD. [ABSTRACT FROM AUTHOR]

A phenomenon we have termed spontaneous lymphocyte-mediated cytotoxicity (SLMC) by non-thymus-derived lymphocytes from normal donors has been described. The phenomenon can be demonstrated using human and xenogeneic (mouse) cell lines as the target cell in a microplate 51Cr release assay which is simple and reproducible. In this paper, SLMC against xenogeneic targets has been evaluated as a potential marker of lymphocytotoxic function with respect to; (a) the nature of the target cell; (b) the variability of the cytotoxic function of lymphocytes from different donors, and from the same donor tested on different days: (c) the nature of the effector cell. Using buoyant density centrifugation of iron plus magnet-purified lymphocytes forming rosettes with sheep red blood cells (SRBC) (T cells) or SRBC--rabbit 19S anti-SRBC--mouse complement (complement receptor lymphocytes), it has been demonstrated that the cytotoxic activity lies in the non-T-lymphocyte fraction, and is probably caused by the complement receptor-bearing lymphocyte. The potential usefulness of this phenomenon as a functional marker of non-T-lymphocyte cytotoxic ability, and for the assessment of serological factors which may affect this cytotoxicity, has been discussed. [ABSTRACT FROM AUTHOR]

In previous in vitro studies the DNA synthesis in human blood lymphocytes induced by low concentration of PWM correlated with the percentage of hone marrow-derived (B) lymphocytes in cell suspensions. No correlation with lymphocyte subpopulations was noted when lymphocytes were activated by high concentrations of PWM. In this paper the hypothesis that low concentration of PWM mainly activates B lymphocytes was tested by measuring the (14C]thymidine incorporation into purified T or B lymphocytes from healthy donors. H lymphocytes were purified to 90-95°, by buoyant density centrifugation of T lymphocytes rosetted with sheep red blood cells. T lymphocytes were enriched by passage of lymphocytes through an IgG-anti-IgG-coated column. Low concentration of PWM-stimulated B lymphocytes but not T lymphocytes. while high concentrations of the stimulant activated both cell types. It was also noted that the B- hut not the T-lymphocyte fraction contained cells which synthesized DNA in the absence of PWM. [ABSTRACT FROM AUTHOR]

Mitogen-transformed human peripheral blood lymphocytes and tonsil blasts were examined by rosette formation to detect the presence of membrane-bound immunoglobulin (Ig) and surface receptors for fixed IgG and fixed C3. In addition, the capacity of these cells to rosette with sheep erythrocytes was evaluated as a reaction characteristic of T lymphocytes. In order for clear morphological recognition of the rosetting transformed lymphocytes and the rosetting tonsil blasts a cytocentrifuge technique was developed and used in conjunction with autoradiography and/or with Romanowsky stains. Using these techniques and the culture methods described in this paper phytohaemagglutinin, pokeweed mitogen, streptococcal filtrates and purified protein derivative stimulated predominantly T cells in the peripheral blood of man. A minority of the transformed cells in these mitogen-stimulated cultures (<24%) did rosette with B lymphocyte markers and presumably represent a B-cell response. No significant differences were found between the T- or B-cell specificity of the mitogens investigated. Lymphoid preparations from tonsils excised from normal donors with recurrent tonsillitis were found to contain 6-15% lymphoblasts and the iarge majority of these cells formed rosettes with the B-cell markers, less than 20% of these lymphoblasts formed spontaneous sheep erythrocyte rosettes. Using a mixed rosetting technique a small proportion (<5%) of PHA-transformed cells and tonsil lymphoblasts were found to have combined sheep Fc or combined sheep C3 receptors. The investigation of B- and T-lymphocyte surface markers on mitogentransformed lymphocytes was extended to neopiastic lymphocyte populations and it was found that the majority of transformed cells (>70%) present in chronic lymphocytic leukaemia cultures stimulated with PHA after 6 days incubation were transformed T lymphocytes. [ABSTRACT FROM AUTHOR]

Target cell killing by lymphocytes can be induced by appropriate antibody complexed to target cell antigens. In this paper it is shown that this form of lymphocyte mediated cytotoxicity is susceptible to inhibition by third party immune complexes which compete with target cell bound antibody for receptors for immunoglobulin on the cytotoxic lymphocytes. The physical state of the complexes is investigated in relation to their inhibitory efficiency. Evidence is presented to show that soluble complexes which exist in antigen-antibody equilibrium or slight antigen excess are the most effective inhibitors. No evidence could be obtained to support the hypothesis that soluble immune complexes can induce indiscriminate cytotoxic activity in lymphocytes. The biological significance of this effect is discussed in relation to chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

The restorative action of developmental hormones, mainly somatotropic hormone, and of lymphnode lymphocytes on the immunologically crippled hypopituitary Snell-Bagg dwarf mouse is evaluated. The hormonal treatment can completely reconstitute the structure of the thymus and of the peripheral lymphoid tissues. Both hormones and mature lymphocytes restore the impaired capacity of the dwarf mouse to propuce antibody and to reject skin allografts. Normal donor thymocytes and bone marrow cells alone or in combination fail to produce the same effect in absence of a hormonal treatment. The action of hormones is not exerted if dwarf mice are thymectomized in adult age. This and other evidence shows that the action of hormones is mediated through the thymus and leads to the formation of longliving lymphocytes. [ABSTRACT FROM AUTHOR]

In a previous paper it had been shown that up to 40% of human peripheral lymphocytes will make rosettes with sheep red cells. In this study the inhibitory effect of antilymphocyte serum (ALS) and of certain other preparations on this rosette phenomenon is described. ALS was prepared in horses by injection of human peripheral lymphocytes and rosette-inhibiting, cytotoxic and agglutinating titres were determined during immunization. The ALS had been tested in vivo by regional administration to vervet monkeys bearing skin allografts. It was found t h a t the peak of rosette-inhibiting titre appeared to provide a good index of immunosuppressive activity. These peaks, and the accompanying periods of immunosuppressive activity, were of short duration, in contrast to the levels of cytotoxic and agglutinathig titres. Antihuman lymphocyte sera had considerable rosette-inhibiting titres against the lymphocytes of the baboon (Papio papio) but little against those of the vervet monkey (Cercopithecus aethiops). Inhibition by ALS of the phenomenon described by us is unaffected by complement. Antihuman globulin serum and phytohaemagglutinin had no inhibitory effect. Digestion of ALS with pepsin to obtain the F (ab')2 fragment had only a slight effect on rosette-inhibiting titres, while it reduced the cytotoxic activity very considerably. The phenomenon described by us is probably different from that reported by other workers, in which only a small proportion of lymphocytes form rosettes. [ABSTRACT FROM AUTHOR]

This paper describes technical details of a micro-reaction for the in vitro detection of agglutinating potency of antilymphocytic serum produced in rabbits with chicken, rat and dog thymus cells, The titration of antilymphocytic serum includes the use of microtitre plastic plates and lymphocytes treated with formalin and stained with trypan blue stain. Formalinized and stained lymphocytes represent a stable antigen of long durability, and the application of those cells in leucoagglutination increases the accuracy and sensitivity of the reaction. [ABSTRACT FROM AUTHOR]

The article focuses on the production of immunoglobins in human peripheral blood lymphocytes in vitro. The peripheral blood lymphocytes of normal humans show an increased production of immunoglobins in vitro after non-specific stimulation by phytohaemagglutinin (PHA) by paper electrophoresis, immunoelectrophoresis and autoradiography that PHA stimulated human lymphocytes which could synthesize immunoglobulin. The synthesis of immunoglobulins was confirmed by the precipitation of C-labelled protein with specific antisera and sodium sulphate. Even in the absence of an added stimulant, normal human lymphocytes synthesized in vitro small amounts of IgG, IgA and IgM as demonstrated by fluorescence, immunoelectrophoresis and autoradiography.

Summary: The immune system is composed of a variety of different T-cell lineages distributed through both secondary lymphoid tissue and non-lymphoid tissue. The intestinal epithelium is a critical barrier surface that contains numerous intraepithelial lymphocytes that aid in maintaining homeostasis at that barrier. This review focuses on T-cell receptor αβ (TCRαβ) CD8αα intraepithelial lymphocytes, and how recent advances in the field clarify how this unique T-cell subset is selected, matures, and functions in the intestines. We consider how the available evidence reveals a story of ontogeny starting from agonist selection of T cells in the thymus and finishing through the specific signaling environment of the intestinal epithelium. We conclude with how this story raises further key questions about the development of different ontogenic waves of TCRαβ CD8αα IEL and their importance for intestinal epithelial homeostasis. The intestine is home to a variety of T-cell subsets. One particular T-cell subset, TCRαβ CD8αα intraepithelial lymphocytes (IELs), is selected in the thymus. This review discusses the factors and events that regulate the selection of TCRαβ CD8αα IELs. [ABSTRACT FROM AUTHOR]

Optic neuritis, a primary clinical manifestation commonly observed in multiple sclerosis (MS), is a major factor leading to permanent loss of vision. Despite decreased vision (optic neuritis), diplopia, and nystagmus, the immunopathology of the optic nerve in MS is unclear. Here, we have characterized the optic nerve pathology in a large cohort of MS cases (n = 154), focusing on the immune responses in a sub-cohort of MS (n = 30) and control (n = 6) cases. Immunohistochemistry was used to characterize the myeloid (HLA-DR, CD68, Iba1, TMEM119, and P2RY12) and adaptive immune cells (CD4, CD8, and CD138) in the parenchyma, perivascular spaces, and meninges in optic nerve tissues from MS and control cases. Of the 154 MS cases, 122 (79%) reported visual problems; of which, 99 (81%) optic nerves showed evidence of damage. Of the 31 cases with no visual disturbances, 19 (61%) showed evidence of pathology. A pattern of myeloid cell activity and demyelination in the optic nerve was similar to white matter lesions in the brain and spinal cord. In the optic nerves, adaptive immune cells were more abundant in the meninges close to active and chronic active lesions, and significantly higher compared with the parenchyma. Similar to brain tissues in this Dutch cohort, B-cell follicles in the meninges were absent. Our study reveals that optic nerve pathology is a frequent event in MS and may occur in the absence of clinical symptoms. Optic neuritis is a primary clinical manifestation commonly observed in multiple sclerosis (MS) and is a major factor leading to permanent loss of vision. Despite decreased vision (optic neuritis), diplopia, and nystagmus, the immunopathology of the optic nerve in MS is unclear. Here, we have characterized the optic nerve pathology in a large cohort of MS cases (n =154), focusing on the immune responses in a sub-cohort of MS (n =30) and control (n= 6) cases. Our study reveals that optic nerve pathology is a frequent event in MS and may occur in the absence of clinical symptoms. [ABSTRACT FROM AUTHOR]

The recently described Ta1 antigen is expressed by activated T cells in vitro and in vivo, as observed in patients with certain immune-mediated diseases, such as multiple sclerosis. In this paper we report on the tissue distribution of the Ta1 antigen. Serological testing of human tumour cell lines and immunohistochemical analysis of human tissue sections revealed a reactivity of the anti-Ta1 antibody with normal and malignant tissues of the upper gastro-intestinal tract, the biliary tract, exocrine pancreas and kidney. SDS-PAGE analysis of immunoprecipitates from 125I-labelled cells, employing the anti-Ta1 antibody, yielded a 113-115 kD band from three serologically Ta1, positive tumour cell lines, from a serologically Ta1, negative human EBV-transformed B lymphoblastoid cell line, from peripheral blood mononuclear cells (PBMC) and, as previously described, a 105 kD band from PHA activated T cells (Fox et al., 1984). After endoglycosidase F treatment similar bands of 85 kD were precipitated from activated T cells and from tumour cell lines. It is therefore likely that very similar glycoproteins,, which differ only modestly in the size of carbohydrate chains, bear the Ta1 epitope on Ta1 positive tissues. [ABSTRACT FROM AUTHOR]

The article information about several authors and their articles published in the 1987 issue of the journal "Clinical & Experimental Immunology." One of the topics is a study on human blood lymphocytes with iC3b (type 3) complement receptors. It is a characterization of subsets which regulate pokeweed mitogen-induced lymphocyte proliferation and immunoglobulin synthesis. Another paper presents a discussion related to the altered monocyte function in patients with benign breast disease. The use of monoclonal antibodies raised against a human IgE myeloma paraprotein for the study of allergen extracts and sera from allergic patients has also been included.

A patient with intestinal lymphangiectasia (IL) was studied for his immunological abnormalities. The patient had hypoproteinaemia with severe hypogammaglobulinaemia. The results of lymphocyte subpopulation studies revealed a decrease of CD4+ cells and a decrease of surface immunoglobulin (sIg)-positive B lymphocytes. T cell functions determined by the proliferative responses against Concanavalin A (Con A) or phytohaemagglutinin (PHA) and by delayed type cutaneous hypersensitivity (DTH) response to purified protein derivatives (PPD) and PHA were normal. No immunoglobulin (Ig)-secreting cells were induced when his peripheral blood lymphocytes (PBL) were cultured with pokeweed mitogen (PWM). His T cells showed suppressor function to the PWM- induced differentiation of normal B cells. This suppressor activity was sensitive to 3000 rads irradiation. His B cells also failed to differentiate into Ig-producing cells with the help of normal T cells and PWM. Thus, in this patient, the decrease of Ig-synthesis in vitro could be attributed to suppressor T cells, lack of T helper cells and an intrinsic B cell defect. Therefore, this patient appears to have immunological abnormalities which differ from previously reported IL patients. [ABSTRACT FROM AUTHOR]

Low concentrations (40 μM) of the purine nucleoside metabolite 2'deoxyguanosine (2'dGuo), were shown to enhance both phytohaemagglutinin- and concanavalin A-induced T cell transformation. Evidence is presented which indicates that this enhancement may he due to the inhibition of suppressor T cell function resulting in the promotion of T cell growth factor production. T cell responses were only inhibited at concentrations of 2'dGuo which were toxic to the lymphocytes. [ABSTRACT FROM AUTHOR]

Peripheral blood lymphocytes (PBL) from a proportion of grass-sensitive patients. studied during or immediately after the grass pollination period, showed spontaneous production in vitro of grass-specific IgE antibody, whereas PBL from atopic patients sensitive to allergens other than grass pollens or non-atopic individuals did not. Pre-incubation of IgE antibody producing PBL from grass-sensitive patients with minute amounts of a mixed grass pollen (MGP) extract or Rye grass antigen Group I (Rye I) usually resulted in a reduction of the spontaneous production in vitro of IgE protein and in a marked inhibition of the spontaneous production in vitro of grass-specific IgE antibody. This antigen-specific inhibition was not mediated by T lymphocytes, but it was apparently due to a signal directly delivered by antigen to the spontaneously IgE antibody producing cells. The results support the concept that the activity of cells responsible for the persistent IgE antibody formation in vitro in atopic patients can be modulated by antigen. [ABSTRACT FROM AUTHOR]

Trypsin treatment of chronic lymphocytic leukaemia (CLL) cells which have the capacity to rosette with mouse erythrocytes (M), the BM+ subtype, inhibits their capacity to rosette and releases a substance into the supernatant which agglutinates mouse and rat erythrocytes but not erythrocytes of five other species tested. This substance has been named immature B-cell lectin (IBL). The specificity of IBL was further demonstrated by fluorescence labelling, absorption and latex rosetting. IBL does not bind to pronasetreated M (pro M), indicating that it has the specificity of R1 as distinct from R1 which binds lo a pronase-resistant ligand on M. Other evidence that I BL is associated with B-cell membrane receptors for mouse erythrocytes is as follows: (1) The amount of IBL released into the supernatant correlated with the trypsin sensitivity of M resetting with different clones of BM+ CLL cells. (2) Only small amounts of IBL were released from non-rosetting cells (T ceils and mature B cells). (3) Binding properties of IBL were inhibited by extract of M but not extract from ox erythrocytes. (4) High-titre solutions of IBL conferred the capacity to form M rosettes on certain types of non-rosetting B cells. IBL has a dual binding specificity. Its binding to M is inhibited by fetuin and mannan, while its binding to B ceils is not inhibited by these substances. The relationship of IBL to other membrane lectins including fibro nectin is discussed. Preliminary characterization indicates a high-molecular-weight (at least 300,000 daltons) glycoprotein which has a pronounced tendency to aggregate in solution. The relationship of IBL to stages of human B-cell maturation is discussed. [ABSTRACT FROM AUTHOR]

The development of the cell-mediated immune response (CMIR) to antigens prepared from Salmonella typhi was investigated in patients suffering from typhoid fever and in normal healthy subjects. The leucocyte migration inhibition test, blast transformation of lymphocytes and active rosette-forming cells were used for detecting CMIR. Peripheral blood lymphocytes were analysed for the numbers and proportions of B lymphocytes, T lymphocytes and their subpopulations with receptors for IgM (Tμ) or IgG (Tγ) and cells with Fc receptors for IgG. These parameters were correlated with the duration and the severity of illness. The uncomplicated cases of typhoid fever were found to have an intact CMIR as compared to the complicated cases. The ratio of T lymphocyte subpopulations was grossly imbalanced in typhoid patients, the numbers of T lymphocytes and their subpopulations were further altered in the complicated cases as compared to uncomplicated cases. The present study demonstrates a depressed state of CMIR in complicated patients with typhoid fever. CMIR may thus emerge as the cardinal point for recovery in typhoid fever rather than the specific antibodies. The study further demonstrates that imbalance within the subsets of T lymphocytes may be responsible for the depressed state of CMIR in complicated cases of typhoid fever. [ABSTRACT FROM AUTHOR]

Spontaneous IgE production in vitro was investigated in 7-day cultures of unfractionated mononuclear cells (MNC) and MNC subpopulations from atopic patients. Depletion of either phagoctytic or adherent cells decreased the amount of IgE detectable in 7-day culture supernatants, but this decrease was due, at least in part, to a loss of cytophilic IgE. Depletion of immunoglobulin-bearing cells (SIg+) reduced significantly but did not abolish the spontaneous IgE production in vitro. On the other hand, depletion of IgM- bearing lymphocytes (SIgM+) which virtually abolished the production of immunoglobulins of the IgM class, did not change significantly the spontaneous production of IgE. Similarly, no change in the spontaneous production of IgE was found when lymphocyte suspensions were depleted of complement receptor-bearing cells (CR+). In contrast. spontaneous IgE product ion was significantly increased by depict ion of T lymphocytes and this increase did not simply reflect the enrichment for IgE-producing cells caused by the fractionation procedure. No significant change in the spontaneous IgE production was found when small numbers of autologous T lymphocytes were added to B cell fractions, whereas the addition of higher concentrations of autologous T cells induced a marked inhibition of the spontaneous IgE production. On the other hand, the addition in culture of pokeweed mitogen (PWM) resulted in a marked reduction of the spontaneous IgE production by B cells, also in the presence of small concentrations autologous T lymphocytes. Normal T cells were consistently effective in inducing a partial inhibition of the spontaneous IgE production by B cells from atopic patients. whereas T cells from a noticeable proportion of atopic patients were not. These data suggest that MNC responsible for the spontaneous IgE production in atopic subjects arc SIgM- and CR-deficient well-differentiated lymphocytes which probably represent the result of an activation which has occurred in vivo. However, this spontaneous IgE production can still be influenced by in vitro manipulation. such as variations in T-B cell ratios or addition of PWM. The results here reported also indicate that normal T cells arc generally more effective than T cells from atopic patients in regulating the activity of spontaneous IgE-producing cells present in the blood of atopic subjects. [ABSTRACT FROM AUTHOR]

T and B lymphocytes from blood and tonsils, as well as T and B lymphoid cell lines, phosphorylate deoxyguanosine which is probably the major toxic metabolite in purine nucleoside phosphorylase (PNP) deficiency. T and B cells also have similar activities of purine nucleoside phosphorylase. These findings indicate that the selective T cell defect in patients with PNP deficiency is unlikely to be due to a selective `trapping' of deoxyguanosine by T lymphocytes. [ABSTRACT FROM AUTHOR]

When lymphocytes from healthy donnors were tested as effector cells, the cytotoxic activities observed in spontaneous and in antibody-dependent cell-mediated cytotoxicity were positively correlated. However, with lymphocyte preparations obtained from renal patients, a dissociation between the two activities was occasionally observed. Human natural kilter cells are lymphocytes, with receptors for the Fc fragment of IgG molecules, but with no surface immunoglobulin. Their cytotoxicity is reduced by the presence of granulocytes or monocytes. After separation of resetting and non-rosetting cells with AET- (2-aminoethyIisothiouronium bromide hydro bromide) or neuraminidase-treated sheep erythrocytes, the majority of the activity was recovered in the non-rosetting fraction, but a portion of it was present consistently in the rosetting cell fraction. Cells in the latter fraction also displayed receptors for the Fc fragment of immunoglobulin G. [ABSTRACT FROM AUTHOR]

The previous report of low levels of purine 5'-nucleotidase activity in peripheral blood mononuclear cells (lymphocytes and monocytes) from patients with non-familial adult onset 'variable' primary hypogammaglobulinaemia has been confirmed and the observation extended to include patients with other types of primary immunodeficiency. Patients with sex-linked congenital hypogammaglobulinaemia have values for mononuclear cell 5'-nucleotidase activity which are in the normal range, whereas most cases of non-familial adult onset 'variable' primary hypogammaglobulinaemia have clearly subnormal values. The three patients with isolated IgA deficiency who were tested also had subnormal values. Evidence that the measured enzyme activity is in fact 5'-nucleotidase and independent of interfering phosphatase activities is presented. No significant or consistent alterations in the activities of the following enzymes were detected in mononuclear cells or erythrocytes: adenosine deaminase, purine nucleoside (inosine) phosphorylase, hypoxanthine phosphoribosyltransferase, adenine phosphoribosyltransferase, phospborihosylpyrophosphate (FRPP) synthetase. The erythrocyte PRPP content and the mononuclear cell PRPP amido-transferase activity were normal in the small number of patients in which they were measured. These findings are discussed in the light of the current interest in the inter-relationship between some disorders of purine metabolism and the immunological deficiency syndromes. [ABSTRACT FROM AUTHOR]

Highly purified blood lymphocytes from patients with plasma cell myeloma were tested in different in vitro systems. The patients were untreated or had received a standardized 4-day treatment with melphalan and prednisolone every sixth week. They were tested 5 weeks after the last treatment to minimize the acute toxic effects of the drugs. Lymphocytes from healthy controls were included in each experiment. Stimulation of lymphocytes was measured by incorporation of 14C-thymidine into DNA after activation with phytohaemagglutinin (PHA), concancavalin A (Con A) and pokeweed mitogen (PWM). Their cytotoxicity was tested against Chang cells (human cell line) and chicken red blood cells in presence of PHA or heat-inactivated rabbit antibodies to target cell antigens. Lysis was quantitated as release of radio-activity from target cells labelled with 51Cr-chromate. Antibody-induced cytotoxicity of lymphocytes from untreated patients was normal or slightly elevated while that of treated patients was severely depressed. Also, lymphocytes from treated patients were significantly less stimulated to DNA synthesis by PWM than were control lymphocytes. PHA-induced cytotoxicity and stimulation of lymphocytes by Con A or PHA were normal in all groups. These results suggest that treatment of myeloma patients with melphalan and cortisone selectively impairs lymphocytes which respond to PWM by DNA synthesis and which participate in antibody-mediated cytolysis. [ABSTRACT FROM AUTHOR]

In vitro transformation of stimulated lymphocytes is frequently evaluated from their ability to incorporate thymidine. This technique measures only one pathway by which cells synthesize DNA-thymine. The purpose of this study was to evaluate the incorporation of various precursors into the DNA-thymine of stimulated leucocytes. It was found that the uptake of thymidine did provide an adequate assessment of total precursor incorporation. [ABSTRACT FROM AUTHOR]

Summary: Immune checkpoint therapy to reverse natural killer (NK) and T cell exhaustion has emerged as a promising treatment in various cancers. While anti‐programmed cell death 1 (PD‐1) pembrolizumab has recently gained Food and Drug Administration (FDA) approval for use in recurrent or metastatic cervical cancer, other checkpoint molecules, such as T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine‐based inhibition motif (ITIM) domains (TIGIT) and T cell immunoglobulin and mucin‐domain containing‐3 (Tim‐3), have yet to be fully explored in this disease. We report expression of TIGIT, Tim‐3 and PD‐1 on subsets of peripheral blood NK (CD56dim/negCD16bright/dim/neg and CD56brightCD16dim/neg) and T cells. The percentages of these cells were increased in women with cervical cancer and pre‐malignant lesions. PD‐1+ NK and T cells were likely to co‐express TIGIT and/or Tim‐3. These cells, with an apparently 'exhausted' phenotype, were augmented in patients. A subset of cells were also natural killer group 2 member D (NKG2D)‐ and DNAX accessory molecule 1 (DNAM‐1)‐positive. PD‐1int and PD‐1high T cells were notably increased in cervical cancer. Soluble programmed cell death ligand 1 (PD‐L1) was higher in cancer patient blood versus healthy donors and we observed a positive correlation between sPD‐L1 and PD‐1+ T cells in women with low‐grade lesions. Within the cancer group, there were no significant correlations between sPD‐L1 levels and cervical cancer stage. However, when comparing cancer versus healthy donors, we observed an inverse association between sPD‐L1 and total T cells and a correlation between sPD‐L1 and CD56dim NK cells. Our results may show an overview of the immune response towards pre‐cancerous lesions and cervical cancer, perhaps giving an early clue as to whom to administer blocking therapies. The increase of multiple checkpoint markers may aid in identifying patients uniquely responsive to combined antibody therapies. [ABSTRACT FROM AUTHOR]

The article presents correction to several articles which have been published in previous editions of the journal "Clinical and Experimental Immunology." The penultimate paragraph of the Discussion on page 7 of the article "Quantitative assessment of the effects of platelet depletion in the autologous phase of nephrotoxic serum nephritis," should read as: In the 'telescoped' model serum C3 did not fall as markedly in the platelet depleted animals as it did in the normal ones. Another correction pertains to Materials and Methods section.

Summary: Tissue‐resident memory T (TRM) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty‐three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in‐vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin‐expressing TRM cells. Surprisingly, programmed cell death 1 (PD‐1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin‐15 and T cell receptor stimulation, perforin and T‐bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy. [ABSTRACT FROM AUTHOR]