CD4+ and CD8+ Distribution Profile in Individuals Infected by Schistosoma mansoni

Rationale: Patients with chronic Schistosoma mansoni infection show lower anti‐soluble egg antigen (SEA) proliferation responses and higher responses to soluble worm antigen preparation (SWAP). Objective: To compare the activation status and proliferation response of peripheral blood mononuclear cells (PBMC) of infected (XTO) and egg‐negative individuals (NI) living in the same endemic area. Methods: XTO (n = 51) and NI individuals from the same geographical area (n = 37) and healthy blood donors (n = 22) were evaluated before and after stimulation with SEA and SWAP. The expression of activation markers (CD4⁺ HLADR⁺, CD8^high+HLA‐DR⁺ and CD8⁺ CD28⁺) and proliferation assay was assessed by flow cytometry. Findings: PBMC from infected patients showed lower frequency of CD4⁺ but no change in CD8⁺ T cells when compared with the healthy donor group. The ratio CD4⁺/CD8⁺ was 1.3, 0.6 and 0.5 in healthy donors, infected and non‐infected individuals, respectively. The HLA‐DR⁺ expression on CD8⁺ was higher in PBMC from infected and non‐infected individuals than from healthy donors, but similar in both total lymphocytes and CD4⁺ populations. No intergroup proliferation response differences were observed in CD4⁺ and CD8⁺ PBMC unstimulated and stimulated with SEA and SWAP. The SEA but not SWAP‐stimulated cells showed a decrease in the expression of phosphorylated extracellular signal‐regulated kinase (ERK1/2). Conclusions: XTO and NI individuals living in the same area presented a smaller per cent of CD4⁺ and a higher per cent of CD8⁺ cells. The activation by either CD8^high+HLA‐DR⁺ or CD8^high+HLA‐DR⁺/CD8⁺ was enhanced and decreased in XTO and NI by CD8⁺ CD28⁺ and CD8⁺ CD28⁺/CD8⁺ when compared with healthy donor. ERK phosphorylation was attenuated in XTO and NI individuals when stimulated with SEA but not SWAP.     

JNK and p38 MAP kinases in CD4+ and CD8+ T cells

Summary: The c‐Jun aminoterminal kinase (JNK) and p38 mitogen‐activated protein (MAP) kinase signaling pathways have been associated with cell death, differentiation and proliferation. CD4⁺ and CD8⁺ T cells have different effector functions after antigen stimulation and control specific aspects of the immune response. The studies carried out in our group indicate that the role of JNK and p38 MAP kinases in CD4⁺ T cells is different from their role in CD8⁺ T cells. Moreover, these two pathways are not redundant in either T cell population. We have also shown that p38 MAP kinase regulates early stages of T cell development in the thymus. It is therefore important to consider the specific function of these kinases in each T cell population when pharmacological inhibitors of JNK and p38 MAP kinases are used for therapeutic purposes to control the immune response.     

Linomide Enhances Apoptosis in CD4+CD8+ Thymocytes

Linomide, a quinoline-3-carboxamide, has a pleiotropic immune modulating capacity and inhibits development as well as progression of disease in animal models of autoimmunity. Linomide treatment of mice resulted in a dramatic, dose-dependent decrease of the thymic cell number shortly after the start of administration. Flow cytometric analysis revealed that the major thymocyte subset, the early immature type CD4⁺CD8⁺ thymocytes, were reduced in number by 75%, mature CD4⁺CD8^? or CD4^?CD8⁺ thymocytes were less sensitive to treatment. The polyclonal T cell activator Con A (Concanavalin A) was used together with IL-2 to evaluate the potential proliferative responsiveness of ex vivo thymocytes. Thymocytes from mice treated with Linomide exhibited a more vigorous proliferation than control cultures. An effect shown to not only be due to the enrichment of mature thymocytes in the cultures from Linomide treated animals, but also when purified, mature thymocytes (CD4⁺CD8^? and CD4^?CD8⁺) were cultured with Con A and IL-2, these cells responded with a significantly enhanced proliferation. In vivo Linomide treatment did not result in increased plasma concentrations of corticosterone and treatment of adrenalectomized mice resulted in a reduction of thymocytes which was comparable to the effect in intact mice, indicating that glucocorticoids (GC) are not major mediators of Linomide-induced thymocyte deletion. In addition to this, and supporting a glucocorticoid independent mode of action, Linomide treatment of thymocytes in vitro resulted in a significant increase in the number of apoptotic cells, specifically in the CD4⁺CD8⁺ subset, implicating apopotosis as one component in the course of thymocyte reduction. In addition to this, in vivo treatment with Linomide resulted in an identical pattern to that seen in vitro in that there was significantly increased apoptosis only in the CD4⁺CD8⁺. These data indicate that Linomide modifies thymocyte development using a glucocorticoid independent pathway and results in the increased apoptosis of the CD4⁺CD8⁺ subset.     

The effect of disodium cromoglycate (DSCG) on in vitro proliferation of CD4+, CD8+, and CD19+ cell populations derived from allergic and healthy donors

The effect of disodium cromoglycate (DSCG) on in vitro proliferation of CD4⁺ and CD8⁺ T cells and CD19⁺ B cells, positively selected by immunomagnetic separation, was investigated. The cells were obtained from allergic patients with moderate serum IgE levels and mild to moderate atopic dermatitis, and healthy controls. The different cell subfractions were stimulated with mitogens or specific allergens, as well as cell supernatants from the lymphoblastoid B- (RPMI 8866) and T-hybridoma (166 A₂) cell lines. Proliferative responses of T- and B-cell subsets stimulated with mitogens together with recombinant interleukin-2 (rIL-2) or accessory cells (AC) could be inhibited by DSCG. In allergic individuals, significant allergen-specific stimulation could be observed in the CD8-depleted peripheral blood mononuclear cell (PBMC) fractions. Isolated CD4⁺ T cells, without AC or IL-2, could also be stimulated with specific allergen, but the responses were rather low. DSCG inhibited, concentration dependently, all allergen-induced responses. Interestingly, only atopic derived CD4⁺ and CD8⁺ T cells were stimulated by soluble low-affinity IgE receptor (Fc?RII/sCD23) and IgE binding factor (IgEBF), including IgE enhancing factor, present in culture supernatants from RPMI 8866 and 166 A₂, respectively. These responses were also inhibited by DSCG. This was in contrast to the amplifying effect of DSCG on spontaneously proliferating RPMI 8866 and 166 A₂ cells, cultured in fresh cRPMI 1640 medium without sCD23 and IgE enhancing factor. Our results show that DSCG delivers an inhibitory signal or signals to PBMC subpopulations expressing Fc?RII/sCD23, either upregulated by phytohemagglutinin in normal and atopic cells, or by allergens or sCD23 in atopic cells. The findings suggest that sCD23 in supernatants or in serum may reverse the general inhibitory mode of DSCG.     

Increased Frequencies of the CD29 and CD57 Markers and Decreased Frequency of CD45RA Within CD4+ and CD8+ Subsets after Allogeneic Bone Marrow Transplantation in Man

Two monoclonal antibodies, anti-CD45RA and anti-CD29, reciprocally divide the CD4⁺ and CD8⁺ lymphocytes into CD4⁺ CD45RA⁺, CD4⁺ CD29⁺, CD8⁺ CD45RA⁺ and CD8⁺ CD29⁺ subsets. The CD4⁺ CD45RA⁺, CD4⁺ CD29⁺ and CD8⁺ CD45RA⁺ possess suppressor-inducer, helper-inducer and suppressor-effector functions respectively. Since the role of these subsets has not been established after allogeneic bone marrow transplantation we studied lymphocyte subpopulations in 12 patients 45- 227 days after the procedure. The fraction of CD4⁺ lymphocytes was significantly (P= 0.0005) decreased to 20±9% versus 43±3% in controls. Within the CD4⁺ compartment, we found an increase in the fraction of CD4⁺ cells that co-expressed CD29 (CD29⁺/CD4⁺) to 92±10% versus 48±15% (P=0.008) in controls and a concommittant decrease m CD45RA⁺/CD4⁺ to 16±12% versus 56±25% (P=0.008) Patients were also noted to have an increase in the percentage of CD8⁺ lymphocytes to 41±5% compared to 23±4% in controls (P=0.0004), Examination of the CD8⁺ subsets revealed a significant increase in the CD29⁺/CD8⁺ fraction to 97±3% versus 64±2% in controls (P= 0.008) and a decrease in the CD45RA⁺/CD8⁺ fraction to 36±11% versus 70±21% (P= 0.008). The number of cells co-expressing CD57 were also determined within the CD4⁺ and CD8⁺ subsets. In patients CD57⁺/CD4⁺ were increased to 29±7% versus 1±1% in controls (P=0.04), and CD57⁺/CD8⁺ to 49±12% versus 23±9% (P=0.02). Since CD29⁺ and CD57⁺ cells have a poor capability for IL-2 production and proliferation this shift in subset distribution may account for some of the defects in cellular immunity seen within the first year after allogeneic bone marrow transplantation.     

A Functional Study of Purified CD4+ and CD8+ Cells Isolated from Synovial Fluid of Patients with Rheumatoid Arthritis and Other Arthritides

The purpose of this investigation was to study purified synovial fluid (SF) CD4⁺ and CD8⁺ cells from patients with rheumatoid arthritis (RA) and other inflammatory joint diseases (non-RA) with respect to the proliferative response to mitogens and recombinant interleukin 2 (rIL-2). Highly purified cell subsets were isolated by an immunomagnetic technique, and spontaneous proliferation as well as proliferative responses to rIL-2 and a combination of phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) (to substitute for accessory cells) were measured. Some patients had SF CD4⁺ and/or CD8⁺ cells with moderately increased spontaneous proliferation, but only the CD4⁺ cells of the two patient groups differed significantly from the peripheral blood (PB) T-cell subsets of healthy individuals who served as controls. The response to rIL-2 was variable but generally low, although about 50% of the CD4⁺ and 20% of the SF CD8⁺ cells of both patient groups expressed the Tac antigen. The response to PHA/PMA was significantly lower for RA SF CD4⁺ cells than for non-RA SF CD4⁺ cells, which again was lower than for normal PB CD4⁺ cells. SF CD8⁺ response to PMA/PHA by both groups of patients was somewhat decreased, but not significantly lower than in the controls. Thus, the CD4⁺ cells seemed functionally more deviant than the CD8⁺ cells in both patient groups, but the abnormality was most pronounced in the RA group. The results demonstrate that the previously reported diminished response to mitogens by SF mononuclear cells is present even when SF CD4⁺ cells are cultured alone. This indicates that these T cells have a reduced response, probably because of prior activation.     

CD4+ memory T cells: functional differentiation and homeostasis

Summary: CD4⁺ T cells are central regulators of both humoral and cellular immune responses. There are many subsets of CD4⁺ T cells, the most prominent being T‐helper 1 (Th1), Th2, Th‐17, and regulatory T cells, specialized in regulating different aspects of immunity. Without participation by these CD4⁺ T‐cell subsets, B cells cannot undergo isotype switching to generate high‐affinity antibodies, the microbicidal activity of macrophages is reduced, the efficiency of CD8⁺ T‐cell responses and CD8⁺ T‐cell memory are compromised, and downregulation of effector responses is impaired. It therefore stands to reason that memory CD4⁺ T cells are likely to fulfill an important facilitator role in the maintenance and control of protective immune responses. This review discusses some issues of importance for the generation of memory CD4⁺ T cells and focuses in particular on their heterogeneity and plasticity, with respect to both phenotypic characteristics and function. Finally, we discuss a number of factors that affect long‐term maintenance of memory CD4⁺ T cells.     

Developing and maintaining protective CD8+ memory T cells

Summary: A critical aim of vaccine‐related research is to identify the mechanisms by which memory T cells are formed and maintained over long periods of time. In recent years, we have designed experiments aimed at addressing two key questions: (i) what are the factors that maintain functionally responsive CD8⁺ memory cells over long periods of time, and (ii) what are the signals during the early stages of infection that drive the differentiation of long‐lived CD8⁺ memory T cells? We have identified a role for CD4⁺ T cells in the generation of CD8⁺ T‐cell‐mediated protection from secondary challenge. While CD4⁺ T cells appear to play a role in the programme of CD8 memory, we find that they are also required for the long‐term maintenance of CD8⁺ memory T‐cell numbers and function. This property is independent of CD40–CD40L interactions, and we propose a role for CD4⁺ T cells in maintaining the ability of CD8⁺ memory T cells to respond to interleukin‐7 (IL‐7) and IL‐15. By manipulating both the time course of infection and the timing of antigen presentation to newly recruited CD8⁺ T cells, we also demonstrate that the programming of effector and memory potential are at least partially distinct processes.     

CD4+CD25+ T cell depletion impairs tolerance induction in a murine model of asthma

Background Regulatory T cells (Tregs) are key players in controlling the development of airway inflammation. However, their role in the mechanisms leading to tolerance in established allergic asthma is unclear. Objective To examine the role of Tregs in tolerance induction in a murine model of asthma. Methods Ovalbumin (OVA) sensitized asthmatic mice were depleted or not of CD25⁺ T cells by anti‐CD25 PC61 monoclonal antibody (mAb) before intranasal treatment (INT) with OVA, then challenged with OVA aerosol. To further evaluate the respective regulatory activity of CD4⁺CD25⁺ and CD4⁺CD25^? T cells, both T cell subsets were transferred from tolerized or non‐tolerized animals to asthmatic recipients. Bronchoalveolar lavage fluid (BALF), T cell proliferation and cytokine secretion were examined. Results Intranasal treatment with OVA led to increased levels of IL‐10, TGF‐β and IL‐17 in lung homogenates, inhibition of eosinophil recruitment into the BALF and antigen specific T cell hyporesponsiveness. CD4⁺CD25⁺Foxp3⁺ T cells were markedly upregulated in lungs and suppressed in vitro and in vivo OVA‐specific T cell responses. Depletion of CD25⁺ cells before OVA INT severely hampered tolerance induction as indicated by a strong recruitment of eosinophils into BALF and a vigorous T cell response to OVA upon challenge. However, the transfer of CD4⁺CD25^? T cells not only suppressed antigen specific T cell responsiveness but also significantly reduced eosinophil recruitment as opposed to CD4⁺CD25⁺ T cells. As compared with control mice, a significantly higher proportion of CD4⁺CD25^? T cells from OVA treated mice expressed mTGF‐β. Conclusion Both CD4⁺CD25⁺ and CD4⁺CD25^? T cells appear to be essential to tolerance induction. The relationship between both subsets and the mechanisms of their regulatory activity will have to be further analyzed.     

Role of TCR specificity in CD4+CD25+ regulatory T-cell selection

Summary: CD4⁺CD25⁺ regulatory T cells play a crucial role in preventing autoimmune disease and can also modulate immune responses in settings such as transplantation and infection. We have developed a transgenic mouse system in which the role that T‐cell receptor (TCR) specificity for self‐peptides plays in the formation of CD4⁺CD25⁺ regulatory T cells can be examined. We have shown that interactions with a single self‐peptide can induce thymocytes bearing an autoreactive TCR to undergo selection to become CD4⁺CD25⁺ regulatory T cells and that thymocytes bearing TCRs with low affinity for the selecting peptide do not appear to undergo selection into this pathway. In addition, thymocytes with identical specificity for the selecting self‐peptide can undergo overt deletion versus abundant selection to become CD4⁺CD25⁺ regulatory T cells in response to variations in expression of the selecting peptide in different lineages of transgenic mice. Finally, we have shown that CD4⁺CD25⁺ T cells proliferate in response to their selecting self‐peptide in the periphery, but these cells do not proliferate in response to lymphopenia in the absence of the selecting self‐peptide. These studies are determining how the specificity of the TCR for self‐peptides directs the thymic selection and peripheral expansion of CD4⁺CD25⁺ regulatory T cells.     

Cyclic nucleotide phosphodiesterase isoenzyme activities in human alveolar macrophages

Background Alveolar macrophages and their precursors, the monocytes are involved in airway inflammation in asthma. An increase in intraceliular cAMP by PDE inhibitors is known to suppress macrophage and monocyte functions. A comparison of the PDE-isoenzyine profiles of human alveolar macrophages from normal and atopic donors and of human peripheral blood monocytes might form a basis to differentially affect functions of these cells by PDE inhibitors. Objective The study compares the PDE isoenzyme activity profiles of human alveolar macrophages from normal and atopic asthmatic donors and human peripheral blood monocytes. In addition, the effect of in vitro maturation of monocytes on their PDE isoenzyme profile is studied. Methods Macrophages were purified (95-97%) by adherence to plastic, and blood monocytes were purified (88%) by counter-current elutriation. PDE isoenzyme activity profiles were investigated using isoenzyme selective inhibitors and activators. Results In macrophages substantial PDE I activity, which was significantly higher than PDE IIF-V activity was detected and PDE II was absent. PDE III was membrane-bound whereas PDE I, IV and V were soluble. No difference was found between alveolar macrophages of normal donors and atopic asthmatics. Monocytes exclusively contained PDE IV but their in vitro maturation led to a PDE isoenzyme profile similar to that of alveolar macrophages. Conclusion These results indicate that human monocytes and alveolar macrophages are distinct targets for the effects of selective PDE inhibitors while alveolar macrophages from normal and atopic individuals appear to be equally sensitive.     

Expansion of circulating Foxp3+CD25bright CD4+ T cells during specific venom immunotherapy

Background Venom immunotherapy (VIT) induces long‐lasting immune tolerance to hymenoptera venom antigens, but the underlying mechanisms are not yet clarified. Regulatory T cells are thought to play an important role in allergic diseases and tolerance induction during specific immunotherapy. Aim Characterize longitudinally the impact of VIT on the pool of circulating regulatory T cells. Methods Fourteen hymenoptera venom‐allergic patients with severe reactions (grades III–IV) were studied before, 6 and 12 months after starting ultra‐rush VIT. Freshly isolated peripheral blood mononuclear cells were surface stained with a panel of markers of T cell differentiation and intracellularly for CTLA‐4 and Foxp3 and analysed by flow cytometry. foxp3 mRNA was quantified by real‐time PCR. VIT responses were assessed by measuring specific IgG4 and IgE levels. Eleven individuals with no history of insect venom allergy were studied as controls. Results VIT induces a significant progressive increase in both the proportion and the absolute numbers of regulatory T cells defined as CD25^bright and/or Foxp3⁺ CD4⁺ T cells. These changes are not related to alterations in the expression of activation markers or imbalances in the naïve/memory T cell compartments. foxp3 mRNA levels also increased significantly during VIT. Of note, the increase in circulating regulatory T cell counts significantly correlates with the venom‐specific IgG4/IgE ratio shift. Conclusion VIT is associated with a progressive expansion of circulating regulatory T cells, supporting a role for these cells in tolerance induction.     

The role of CD8+ T-cell replicative senescence in human aging

Summary: The strict limit in proliferative potential of normal human somatic cells – a process known as replicative senescence – is highly relevant to the immune system, because clonal expansion is fundamental to adaptive immunity. CD8⁺ T cells that undergo extensive rounds of antigen‐driven proliferation in cell culture invariably reach the end stage of replicative senescence, characterized by irreversible cell‐cycle arrest and a critically short telomere length. Cultures of senescent CD8⁺ T cells also show resistance to apoptosis, permanent loss of CD28 expression, altered cytokine profiles, reduced ability to respond to stress, and various functional changes. Cells with similar characteristics accumulate during normal aging as well as in younger persons infected with human immunodeficiency virus, suggesting that the process of replicative senescence is not an artifact of cell culture but is also occurring in vivo. Interestingly, in elderly persons, the presence of high proportions of CD8⁺ T cells with characteristics of replicative senescence is correlated with reduced antibody responses to vaccines as well as with osteoporotic fractures. CD8⁺CD28^– T cells also accumulate in patients with certain types of cancer. The emerging picture is that senescent CD8⁺ T cells may modulate both immune and non‐immune functions, contributing not only to reduced anti‐viral immunity but also to diverse age‐related pathologies.     

Apoptosis among CD45RA−/low CD3+ Progeny Accompanies Differentiation of Human Multinegative Thymocytes

Apoptotic cell death is widely believed to be the fate of negatively selected cells in the thymus. In this work we have used multiparameter flow cytometry to analyse reductions in DNA content that occur among differentiating human CD3^?4^?8^? multinegative (MN) thymocytes as they acquire CD3/TCR during in vitro culture. DNA content was measured as the intensity of the DNA-binding dye DAPI. The position of the diploid peak was identified by comparison to chicken red blood cells and to unfractionated uncultured thymocytes which have a sharply defined diploid peak. Apoptosis, was defined as a reduction in DNA content. Apoptotic cell death occurred continuously throughout the 7 day culture period and at the latest stages of culture DNA fragmentation was apparent on gels. Although both CD3^? and CD3⁺ progeny became apoptotic, it was more frequent among the CD3⁺progeny of the MN thymocytes. Apoptotic progeny included 60–70% CD3⁺ cells, while progeny remaining diploid were 8–36% CD3⁺. Fifty five per cent of CD3⁺ TCRδl⁺ progeny had less than 75% of the diploid DNA content, while for CD3⁺ TCRδ1^? progeny only 28% were in this category. CD3⁺ TCRδ1⁺ progeny also comprised 66% of the cycling cells at days 6–7 of culture, suggesting a pattern of rapid cell division followed by apoptotic cell death for this subset. A lack of positive selection in culture may trigger apoptosis among the TCRδ1 progeny. In contrast, TCRαβ progeny arising in culture appear to be less susceptible to apoptosis, perhaps due to their lack of CD4 and CD8. The expression of CD45RA and CD45R0 isoforms were assessed on the progeny of MN thymocytes based on their DNA content. Although 30% of apoptotic progeny expressed CD45RA, it was present at relatively low density compared to that on diploid or cycling cells, 55% of which were CD45RA^hi. The majority of apoptotic cells expressed neither CD45RA or CD45R0, but were CD45⁺, indicating the presence of an isoform not detected by our monoclonal antibodies (MoAbs). This is consistent with speculations that apoptotic cell death among thymocytes is preceded by a transition in CD45 isoform expression. These conditions may model early selective events resulting from high avidity TCR engagement that is independent of CD4 and/or CD8.     

Dendritic cells expand antigen-specific Foxp3+CD25+CD4+ regulatory T cells including suppressors of alloreactivity

Summary: Thymic derived naturally occurring CD25⁺CD4⁺ T regulatory cells (Tregs) suppress immune responses, including transplantation. Here we discuss the capacity of dendritic cells (DCs) to expand antigen‐specific Tregs, particularly polyclonal Tregs directed to alloantigens. Initial studies have shown that mature DCs are specialized antigen‐presenting cells (APCs) for expanding antigen‐specific CD25⁺ CD4⁺ Tregs from TCR transgenic mice. When triggered by specific antigen, these Tregs act back on immature DCs to block the upregulation of CD80 and CD86 costimulatory molecules. More recently, DCs have been used to expand alloantigen‐specific CD25⁺CD4⁺ Tregs from the polyclonal repertoire in the presence of interleukin‐2 (IL‐2). Allogeneic DCs are much more effective than allogeneic spleen cells for expanding CD25⁺CD4⁺ Tregs. The DC‐expanded Tregs continue to express high levels of Foxp3, even without supplemental IL‐2, whereas spleen cells poorly sustain Foxp3 expression. When suppressive activity is tested, relatively small numbers of DC‐expanded CD25⁺CD4⁺ Tregs exert antigen‐specific suppression in the mixed leukocyte reaction (MLR), blocking immune responses to the original stimulating strain 10 times more effectively than to third party stimulating cells. DC‐expanded Tregs also retard graft versus host disease (GVHD) across full major histocompatibility complex (MHC) barriers. In vitro and in vivo, the alloantigen‐specific CD25⁺CD4⁺ Tregs are much more effective suppressors of transplantation reactions than polyclonal populations. We suggest that the expansion of Tregs from a polyclonal repertoire via antigen‐presenting DCs will provide a means for antigen‐specific control of unwanted immune reactions.     

A subset of CD8+ T cells from allergic patients produce IL-4 and stimulate IgE production in vitro

Background and Objective A subset of IL-4 producing CD8⁺ T cells was recently identified in HIV patients. Based on these findings we examined whether IL-4 producing CD8⁺ T cells would also be present in allergic patients and what would be the functional relevance of this T-cell population. Methods We investigated the role of CD8⁺ T cells in IgE production of allergic diseases by analysing the cytokine profile of individual CD4⁺ and CD8⁺ T cells. Results In allergic patients about twice as many CD4⁺ T cells and six times as many CD8⁺ T cells produced IL-4 as in non-allergic controls. In contrast the frequency of IFNγ⁺ T-cell subsets did not significantly differ between the allergic and non-allergic individuals. The frequency of 1L4⁺CD8⁺ T cells correlated with the level of serum IgE. Coculture experiments with T cells or purified CD8⁺ T cells together with autologous B cells indicated that CD8⁺ T cells enhanced IgE in vitro, but not IgM production, even when they were physically separated from B cells. This effect could be partially blocked by addition of an IL-4 binding protein, a soluble IL-4 receptor indicating that lL-4 is involved in CD8⁺ T-cell mediated IgE production. Conclusions These data indicate a positive role of IL-4 secreting CD8⁺ T cells in IgE regulation in allergic patients.     

CD8+ T‐cell memory in tumor immunology and immunotherapy

Summary: The cellular and molecular mechanisms underlying the formation of distinct central, effector, and exhausted CD8⁺ T‐cell memory subsets were first described in the setting of acute and chronic viral diseases. The role of these T‐cell memory subsets are now being illuminated as relevant to the tumor‐bearing state. The generation and persistence of productive CD8⁺ T‐cell memory subsets is determined, in part, by antigen clearance, costimulation, responsiveness to homeostatic cytokines, and CD4⁺ T‐helper cells. By contrast, chronic exposure to antigen, negative costimulation, and immunomodulation by CD4⁺ T regulatory cells corrupt productive CD8⁺ T memory formation. It has become clear from human and mouse studies that the mere generation of CD8⁺ T‐cell memory is not a ‘surrogate marker’ for cancer vaccine efficacy. Some current cancer vaccine strategies may fail because they amplify, rather than correct or reset, the corrupted CD8⁺ memory population. Thus, much of the present effort in the development of vaccines for cancer and chronic infectious diseases is aimed at creating effective memory responses. Therapeutic vaccines for cancer and chronic infectious diseases may achieve consistent efficacy by ablation of the dysfunctional immune state and the provision of newly generated, non‐corrupted memory cells by adoptive cell transfer.     

Non-malignant clonal expansions of CD8+ memory T cells in aged individuals

Summary: CD8⁺ T cells provide a major line of defense against intracellular pathogens. Upon encounter with antigen, CD8⁺ T cells go through three distinct phases involving proliferation, contraction, and differentiation to become eventually long‐lived CD8⁺ memory T cells. CD8⁺ memory T cells provide long‐term protection against infection by intracellular pathogens. CD8⁺ memory T‐cell proliferation and survival are regulated by many factors, including cytokines, and CD8⁺ memory T cells are stably maintained over a period of months to years. In aged humans and mice, however, there are significant alterations to the CD8⁺ memory T‐cell compartment with frequent development of monoclonal expansions of CD8⁺ memory T cells in healthy individuals. Interestingly, CD8⁺ clonal expansions are not malignant and do not progress to lymphomas, suggesting that these cells must still be under certain constraints. In this review, we discuss our current understanding of factors that contribute to and regulate these CD8⁺ clonal expansions as well as the impact of CD8⁺ clonal expansions on immune function of the aged. In addition, we discuss similarities and differences between CD8⁺ clonal expansions observed in humans and mice, and we postulate that CD8⁺ clonal expansions represent a spectrum of biological outcomes ranging from antigen‐driven to antigen‐independent phenomena.