Down-regulation of CXCR4 expression on human CD8+ T cells during peripheral differentiation

Multi-color flow cytometric analysis on human CD8(+) T cell subsets revealed that CXCR4 is predominantly expressed on CD8(+) T cells with the naive CD27(+)CD28(+)CD45RA(+) phenotype, and is down-regulated during differentiation into those with an effector phenotype. The down-regulation of CXCR4 expression during peripheral differentiation was supported by the fact that the expression of CXCR4 on CD8(+) T cells was negatively correlated with that of perforin. The analysis of CCR5, CCR7, and CXCR4 co-expression further showed that CD8(+) T cells expressing a high level of CXCR4 are CCR7(+)CCR5(-) naive or central memory subsets, and those expressing a low level of CXCR4 were included in the CCR7(-)CCR5(+/-) memory/effector and effector subsets. Epstein Barr virus-specific CD8(+) T cells, which mostly express the memory phenotype, expressed CXCR4, while human cytomegalovirus-specific CD8(+) T cells, which mostly express the effector phenotype, partially expressed this receptor, showing that the expression of CXCR4 is also down-regulated during differentiation of viral antigen-specific CD8(+) T cells. The classification of human CD8(+) T cells based on the expression of these chemokine receptors should prove useful for studies that clarify the differentiation of human CD8(+) T cells.     

Unidirectional development of CD8+ central memory T cells into protective Listeria-specific effector memory T cells

Three distinct subsets of antigen-experienced CD8(+) T cells have been identified so far: short-living effector T cells (T(EC)) and two long-living subsets, described as central (T(CM)) and effector memory (T(EM)) T cells. The lineage relationships of these subpopulations as well as their involvement in protection have not yet been conclusively determined. We recently described a novel marker combination (CD127 and CD62L) to identify all three major CD8(+) T cell subsets in mice infected with Listeria monocytogenes (L.m.). Extensive lineage relationship analyses on highly purified subpopulations after in vitro and in vivo stimulation demonstrated that T(CM) can develop into T(EM) or T(EC), whereas T(EM) can only progress to T(EC) cells. Short-living T(EC) never regained a T(EM) or T(CM) phenotype. These data strongly suggest a hierarchical and unidirectional order of developmental stages. In vivo priming protocols that preferentially induced one of the different CD8(+) T cell subsets demonstrated that predominance of T(EM) (CD40 stimulation) correlated best with effective protection against L.m., whereas generation of neither T(CM) (by immunization with heat-killed L.m.) nor T(EC) (by systemic co-administration of CpG during primary infection) conferred substantial long-term protective immunity. These findings have important implications for the design of more effective T cell-based vaccines.     

Priming of CD8+ T cell responses following immunization with heat-killed Plasmodium sporozoites

Protective immune responses against malaria are induced by immunization with radiation-attenuated Plasmodium sporozoites. In contrast, non-viable, heat-killed sporozoites do not induce protection, emphasizing the requirement for live parasites to achieve effective immune responses. Using an experimental system with CD8+ T cells from T cell receptor-transgenic mice, we analyzed the primary CD8+ T cell responses elicited by heat-killed inactivated sporozoites. We found that the numbers of specific CD8+ T cells induced were much lower compared to when immunizing with attenuated sporozoites; however, the kinetics of activation and the phenotype of these T cells were similar in both groups. Despite their low frequency after priming, high numbers of specific CD8+ T cells were observed after boosting with a recombinant vaccinia virus. Upon induction of the recall response, the same level of protection was observed when either heat-killed or attenuated sporozoites were used for priming. We propose that live parasites are not critical for the induction of memory T cell populations against the malaria liver stages.     

Differences between CD8+ T cells in lupus-prone (NZB x NZW) F1 mice and healthy (BALB/c x NZW) F1 mice may influence autoimmunity in the lupus model

Immunization with portions of a murine antibody to DNA induced Ig peptide-reactive peripheral CD8+ inhibitory T (Ti) cells in non-autoimmune (BALB/c x NZW) F1 (CWF1) mice. Those Ti suppressed in vitro production of IgG anti-DNA by lymphocytes from MHC-matched, lupus-prone (NZB x NZW) F1 (BWF1) mice, primarily via secretion of transforming growth factor-beta (TGF-beta). However, splenic CD8+ cells from immunized BWF1 mice failed to suppress anti-DNA. Therefore, BWF1 mice were studied for defects in peripheral CD8+ T cells. The potential to suppress autoimmunity mediated by activated CD4+ helper T and B cells in BWF1 mice was assessed. As BWF1 mice aged, peripheral CD8+ T cells expanded little; fewer than 10% displayed surface markers of activation and memory. In contrast, quantities of splenic CD4+ T and B cells increased; high proportions displayed activation/memory markers. In old compared to young BWF1 mice, splenic cell secretion of two cytokines required for generation of CD8+ T effectors, IL-2 and TGF-beta, was decreased. Immunizing BWF1 mice activated peptide-reactive CD8+ T cells, but their number was decreased compared to young BWF1 or old normal mice. While peptide-reactive splenic CD8+ T cells from immunized BWF1 mice did not survive in short-term cultures, similar CD8+ T cell lines from immunized CWF1 mice expanded and on transfer into BWF1 mice delayed autoimmunity and prolonged survival. Therefore, CD8+ T cells in old BWF1 mice are impaired in expansion, acquisition of memory, secretion of cytokine, and suppression of autoimmunity. Understanding these defects might identify targets for therapy in systemic lupus erythematosus.     

CD8+ T cell contributions to allergen induced pulmonary inflammation and airway hyperreactivity

The pathogenesis of asthma has been linked to the production of type 2 cytokines, which can be expressed by several cell types in the lung. These studies investigated CD8(+) T cell responses in a murine cockroach antigen (CRA) model of asthma. The results from these present studies show that depletion of CD8(+) T cells after allergen sensitization to CRA significantly reduces airway hyperreactivity, airway eosinophilia and pulmonary type 2 cytokine levels. The data demonstrate that CD8(+) T cells from CRA-sensitized mice can produce type 2 cytokines IL-4, IL-5 and IL-13 upon antigen challenge, and that the transfer of these cells into naive mice will cause airway hyperreactivity when exposed to CRA. We found that the transferred airway response is dependent on both IL-4 and IL-13 from CD8(+) T cells using cytokine knockout mice. Compared to CD4(+) T cells, CD8(+) T cells were not as numerous in the lungs of sensitized and challenged mice, but were as efficacious in the transfer of airway disease. The most severe airway response was observed when both CD4(+) and CD8(+) T cells were transferred at the same time. Altogether, these studies highlight a role for CD8(+) T lymphocytes in the development of allergen-induced airway responses.     

Aging-dependent generation of suppressive CD4+CD25-R123loCD103+ T cells in mice

Advancing age is associated with significant alterations in immune functions, including a decline in CD4 T cell function, in both mice and humans. In our previous report, we showed that CD4(+)CD25(-) T cells in aged (24-month-old) mice, especially after in vitro pre-stimulation of these cells, exhibit hyporesponsive and suppressive properties. We examined here whether the suppressive activity of aged CD4(+)CD25(-) T cells is ascribable to a particular population within these cells. In vitro analyses revealed that cell populations rapidly extruding Rhodamine-123 (R123) (referred to as R123(lo) cells) in aged CD4(+)CD25(-) T cells have a more potent suppressive function compared with R123(hi) populations.In addition, CD103(+) cells in freshly prepared aged CD4(+)CD25(-)R123(lo) T cells had a most potent suppressive activity. Both R123(hi) and R123(lo) populations had individually stronger suppressive activity after pre-stimulation than before pre-stimulation. Furthermore, the R123(lo) population in young CD4(+)CD25(-) T cells also had different properties from R123(hi) T cells: low responsiveness, no additive effect in proliferation assays, and the gain of a suppressive function after in vitro pre-stimulation. Taken together, these results suggest that CD4(+)CD25(-)R123(lo) T cells are a unique population within whole CD4(+)CD25(-) T cells. This population exists in the early stage of the life span, and the properties in this population become obvious with aging, that is the gain of their suppressive activity.     

Incomplete effector/memory differentiation of antigen-primed CD8+ T cells in gene gun DNA-vaccinated mice

DNA vaccination is an efficient way to induce CD8+ T cell memory, but it is still unclear to what extent such memory responses afford protection in vivo. To study this, we induced CD8+ memory responses directed towards defined viral epitopes, using DNA vaccines encoding immunodominant MHC class I-restricted epitopes of lymphocytic choriomeningitis virus covalently linked to beta2-microglobulin. This vaccine construct primed for a stronger recall response than did a more conventional minigene construct. Despite this, vaccinated mice were only protected against systemic infection whereas protection against the consequences of peripheral challenge was limited. Phenotypic analysis revealed that DNA vaccine-primed CD8+ T cells in uninfected mice differed from virus-primed CD8+ T cells particularly regarding expression of very-late antigen (VLA)-4, an adhesion molecule important for targeting T cells to inflammatory sites. Thus, our DNA vaccine induces a long-lived memory CD8+ T cell population that provides efficient protection against high-dose systemic infection. However, viral replication in solid non-lymphoid organs is not curtailed sufficiently fast to prevent significant virus-induced inflammation. Our results suggest that this is due to qualitative limitations of the primed CD8+ T cells.     

Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) has traditionally been thought to be almost exclusively mediated by CD4(+) effector T cells. Here, we provide evidence for the existence of mouse CD8(+) T cells that are specific for an epitope of the myelin oligodendrocyte glycoprotein (MOG). Using a panel of truncated MOG peptides, we have identified the minimal epitope recognized by these T cells as MOG 37-46. This peptide, while possessing relatively low affinity for H-2D(b), efficiently stimulates IFN-gamma production from MOG-specific CD8(+) T cell lines in vitro and induces EAE in vivo. To further characterize the magnitude and kinetics of expansion of the MOG-specific CD8(+) T cell population in vivo, we used MOG 37-50/H-2D(b) MHC tetramers to visualize MOG-specific CD8(+) effectors in the peripheral lymphoid organs and central nervous system during the course of EAE induction and progression. Our results identify MOG-specific CD8(+) T cells in the central nervous system prior to and after the onset of disease, suggesting that CD8(+) T cells are a possible target for therapeutic intervention during EAE.     

Endothelial inducible costimulator ligand expression is increased during human cardiac allograft rejection and regulates endothelial cell-dependent allo-activation of CD8+ T cells in vitro

The role of costimulatory molecules other than CD80/CD86 in endothelial cell (EC)-dependent CD8(+) T cell activation including the generation of a distinct subset of endothelium-specific CTL (EC-CTL) remains unclear. Inducible costimulator (ICOS) and its ligand (ICOSL) are new members of the CD28 family mediating effector T cell differentiation and graft rejection in animal models. In this study endothelial ICOSL expression/regulation and effects on CD8(+) T cell allo-activation were analyzed. Constitutive expression of ICOSL was found on human EC. IL-1alpha and TNF-alpha induced ICOSL in an NF-kappaB-dependent manner on human umbilical vein endothelial cells (HUVEC). ICOS receptor was not detected on resting CD8(+) T cells but was induced in co-cultures with HUVEC. ICOSL blockade reduced CD8(+) T cell proliferation by 70% along with a marked decrease of IL-2 and IFN-gamma production in co-cultures with HUVEC. IL-2 supplementation of co-cultures could overcome the effect of ICOSL blockade; similarly the generation of EC-CTL was not impaired by ICOSL blockade in an IL-2-containing system. In vivo, weak constitutive ICOSL expression was found on coronary microvessels, which was significantly up-regulated during acute cardiac allograft rejection (p=0.04). Our data indicate a distinct role for ICOSL in EC-mediated CD8(+) T cell costimulation with implications for human cardiac allograft rejection.     

Clearance of Theiler's virus infection depends on the ability to generate a CD8+ T cell response against a single immunodominant viral peptide

Theiler's murine encephalomyelitis virus (TMEV) induces a chronic demyelinating disease in the central nervous system of susceptible mice. Resistance to persistent TMEV infection maps to he D locus of the major histocompatibility complex suggesting a prominent role of antiviral CTL in the protective immune response. Introduction of the D(b) gene into the FVB strain confers resistance to this otherwise susceptible mouse line. Infection of the FVB/D(b) mouse with TMEV provides a model where antiviral resistance is determined by a response elicited by a single class I molecule. Resistant mice of the H-2(b) haplotype mount a vigorous H-2D(b)-restricted immunodominant response to the VP2 capsid protein. To investigate the extent of the contribution of the immunodominant T cell population in resistance to TMEV, FVB/D(b) mice were depleted of VP2-specific CD8(+) T cells by peptide treatment prior to virus infection. Peptide-treated mice were not able to clear the virus and developed extensive demyelination. These findings demonstrate that the D(b)-restricted CD8(+) T cells specific for a single viral peptide can confer resistance to TMEV infection. Our ability to manipulate this cellular response provides a model for investigating the mechanisms mediating protection against virus infection by CD8(+) T cells.     

Evolution of diverse antiviral CD8+ T cell populations after murine cytomegalovirus infection

Cytomegalovirus (CMV) is a major human pathogen normally controlled by cellular immune responses. The infection can be modeled in the mouse using murine CMV (MCMV). During the latent phase of infection, two different patterns of CD8(+) T cell responses have been observed: some specificities show increasing frequencies over time ("memory inflation"), while others, which are present acutely, are barely detectable at later time points. This distinction is independent of initial immunodominance. We analyzed the extent to which such responses differ functionally and tracked both their population distribution and their evolution over time. We observed two clear patterns of memory development that diverged early after infection. Acutely, CD8(+) T cells directed against all epitopes showed similar activation, phenotype and distribution. Thereafter, one set of responses ("inflationary") increased in frequency over time, was found in high numbers in non-lymphoid organs and was associated with an activated (CD28(low) CD27(low)CD122(low)) phenotype. In contrast, CD8(+) T cells responses specific for other MCMV epitopes ("non-inflationary") showed a slow reversion to a classical "central" memory phenotype without enrichment in non-lymphoid organs. A simple model to describe the equilibrium state in MCMV is presented, which may point to previously unexplored antiviral populations present after human CMV infection.     

The functional avidity of virus-specific CD8+ T cells is down-modulated in Borna disease virus-induced immunopathology of the central nervous system

Borna disease virus (BDV) infection of the central nervous system (CNS) leads to severe neurological symptoms in susceptible MRL mice. The disease is mainly mediated by CD8+ T cells specific for the immunodominant epitope TELEISSI in the BDV nucleoprotein. In this study, TELEISSI/MHC class I tetramers were used to directly visualize antigen-specific CD8+ T cells. We found that on average approximately 30% of the ex vivo analyzed CD8+ T cells in the CNS of diseased mice were specific for TELEISSI. Unexpectedly, the frequency of tetramer-reactive brain-derived CD8+ T cells doubled following overnight culture in the absence of antigen. The majority of CD8+ T cells showed enhanced tetramer binding without up-regulation of T cell receptor surface expression. The frequency of IFN-gamma-secreting CD8+ T cells after antigen-specific stimulation was higher in overnight cultures than in freshly isolated BDV-specific brain lymphocytes, and enhanced tetramer binding correlated with elevated sensitivity to lower levels of peptide antigen in cytotoxicity assays. These results indicate that the functional avidity of virus-specific CD8+ T cells was down-modulated in vivo. Thus, quantification of tissue-infiltrating CD8+ T cells by the tetramer technique must be interpreted with caution as it may underestimate the real frequency of antigen-specific CD8+ T cells.     

Novel method for detection of virus-specific CD41+ T cells indicates a decreased EBV-specific CD4+ T cell response in untreated HIV-infected subjects

A lower function of EBV-specific CD8(+) T cells in HIV-infected subjects could be related to a lack of specific CD4(+) T cell help. Therefore, we studied EBV-specific CD4(+) T cells in both healthy donors and untreated or highly active antiretroviral therapy (HAART)-treated HIV-seropositive homosexual men. To this end, PBMC were stimulated with overlapping peptide pools from a latent and a lytic EBV protein, EBV nuclear antigen (EBNA)1 and EBV lytic-switch protein ZEBRA (BZLF1), respectively. EBV-specific CD4(+) T cell frequencies measured directly ex vivo were low. To measure EBV-specific memory CD4(+) T cells, capable of both expansion and IFN-gamma production upon antigenic challenge, we developed a specific and reproducible assay, combining ex vivo expansion of specific T cells with flow cytometric analysis of IFN-gamma production. Untreated HIV-infected individuals had a lower CD4(+) T cell response to both EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART-treated HIV-positive subjects. This suggests loss of EBV-specific CD4(+) T cells due to HIV infection, while HAART might restore this response. In addition, we found an increase in the EBNA1-specific CD8(+) T cell response in HAART-treated subjects. Interestingly, numbers of EBV-specific CD4(+) and CD8(+) T cells were inversely correlated with EBV viral load, suggesting an important role also for EBV-specific CD4(+) T cells in the control of EBV infection.     

High frequencies of functionally impaired cytokeratin 18-specific CD8+ T cells in healthy HLA-A2+ donors

Combining cell surface phenotyping with functional analysis, human CD8+ T cells have been divided into several subsets which are being studied extensively in diverse physiological situations, such as viral infection, cancer and ageing. In particular, so-called terminally differentiated effector cells possess a CD45RA+ CCR7- CD27- CD28- phenotype, contain perforin and, in different models, have been shown to exert direct ex vivo killing and to release interleukins upon both antigen-nonspecific and -specific stimulation. Using HLA class I multimers, we have identified a high frequency of peripheral CD8+ T cells that recognize a peptide derived from the self protein cytokeratin 18 presented by the HLA-A*0201 molecule. These cells can be detected in approximately 15% of the HLA-A2-positive healthy donors tested. A detailed analysis revealed that they must have divided extensively in vivo, have an effector cell phenotype and express various natural killer cell-associated receptors. Interestingly, however, they remained unresponsive to antigen-specific stimulation in vitro in terms of cytotoxicity and cytokine secretion. Thus, cytokeratin 18-specific cells constitute a frequently encountered, new CD8+ T lymphocyte subpopulation without classical effector status and with so far unknown function.     

CD8+ T cell-mediated protection against an intracellular bacterium by perforin-dependent cytotoxicity

Growth of Listeria monocytogenes is mainly controlled by macrophages, which are activated by specific T cells. A potential role of CD8⁺ T cells by direct lysis of infected cells was investigated in perforin-deficient mice generated by homologous recombination. The absence of perforin-mediated cytotoxicity resulted in delayed clearance of Listeria from the spleen but not the liver after primary infection, overall susceptibility to Listeria however was not increased. Protection against a secondary infection was drastically impaired in perforin-deficient mice. Adoptive transfer of immune spleen cells to recipients revealed that anti-Listeria protection by CD8⁺ T cells from perforin-deficient versus normal mice was about 10-fold reduced in livers and about 100-fold reduced in the spleen of recipients. CD4⁺ T cells from immune control and perforin-deficient mice conferred comparable protection. These results indicate that the protective effect of CD8⁺ T cells against an intracellular bacterium mainly evident in secondary infection is mediated by a perforin-dependent pathway, presumably cytotoxicity, and less by other direct or indirect effector mechanisms.     

Intestinal double-positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines

Peripheral blood and intestinal CD4+CD8+ double-positive (DP) T cells have been described in several species including humans, but their function and immunophenotypic characteristics are still not clearly understood. Here we demonstrate that DP T cells are abundant in the intestinal lamina propria of normal rhesus macaques (Macaca mulatta). Moreover, DP T cells have a memory phenotype and are capable of producing different and/or higher levels of cytokines and chemokines in response to mitogen stimulation compared to CD4+ single-positive T cells. Intestinal DP T cells are also highly activated and have higher expression of CCR5, which makes them preferred targets for simian immunodeficiency virus/HIV infection. Increased levels of CD69, CD25 and HLA-DR, and lower CD62L expression were found on intestinal DP T cells populations compared to CD4+ single-positive T cells. Collectively, these findings demonstrate that intestinal and peripheral blood DP T cells are effector cells and may be important in regulating immune responses, which distinguishes them from the immature DP cells found in the thymus. Finally, these intestinal DP T cells may be important target cells for HIV infection and replication due to their activation, memory phenotype and high expression of CCR5.     

Autoreactive human peripheral blood CD8+ T cells with a regulatory phenotype and function

Despite substantial advances in our understanding of CD4+ CD25+ regulatory T cells, a possible equivalent regulatory subset within the CD8+ T cell population has received less attention. We now describe novel human CD8+/TCR alphabeta+ T cells that have a regulatory phenotype and function. We expanded and cloned these cells using autologous LPS-activated dendritic cells. The clones were not cytolytic, but responded in an autoreactive HLA class I-restricted fashion, by proliferation and production of IL-4, IL-5, IL-13 and TGFbeta1, but not IFN-gamma. They constitutively expressed CD69 and CD25 as well as molecules associated with CD4+ CD25+ regulatory T cells, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and Foxp3. They suppressed IFN-gamma production and proliferation by CD4+ T cells in vitro in a cell contact-dependent manner, which could be blocked using a CTLA-4-specific mAb. They were more readily isolated from patients with ankylosing spondylitis and may therefore be up-regulated in response to inflammation. We suggest that they are the CD8+ counterparts of CD4+ CD25+ regulatory T cells. They resemble recently described CD8+ regulatory cells in the rat that were able to abrogate graft-versus-host disease. Likewise, human HLA-restricted CD8+ regulatory T cells that can be cloned and expanded in vitro may have therapeutic applications.     

Circulating memory CD8+ T cells are limited in forming CD103+ tissue-resident memory T cells at mucosal sites after reinfection

Tissue-resident memory CD8⁺ T cells (T_RM) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (T_CM) and effector memory CD8⁺ T cells (T_EM) also contribute to tissue recall responses, but their potential to form mucosal T_RM remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of T_CM and T_EM at mucosal sites. Donor T_CM and T_EM exhibited robust systemic recall responses, but only limited accumulation in the small intestine, consistent with reduced expression of tissue-homing and -retention molecules. Murine and human circulating memory T cells also exhibited limited CD103 upregulation following TGF-β stimulation. Upon pathogen clearance, T_CM and T_EM readily gave rise to secondary T_EM. T_CM also formed secondary central memory in lymphoid tissues and T_RM in internal tissues, for example, the liver. Both T_CM and T_EM failed to substantially contribute to resident mucosal memory in the small intestine, while activated intestinal T_RM, but not liver T_RM, efficiently reformed CD103⁺ T_RM. Our findings demonstrate that circulating T_CM and T_EM are limited in generating mucosal T_RM upon reinfection. This may pose important implications on cell therapy and vaccination strategies employing memory CD8⁺ T cells for protection at mucosal sites.     

CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease

Chronic antigenic stimulation leads to gradual accumulation of late-differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8(+) T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8(+) CD28(-) or CD8(+) CD57(+) T lymphocytes. There is growing evidence that the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population is heterogeneous and composed of various functionally competing (cytotoxic and immunosuppressive) subsets thus the overall effect of CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell-mediated immunity depends on the predominance of a particular subset. Many articles claim that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells have lost their proliferative capacity during process of replicative senescence triggered by repeated antigenic stimulation. However recent data indicate that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells can transiently up-regulate telomerase activity and proliferate under certain stimulation conditions. Similarly, conflicting data is provided regarding CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell sensitivity to apoptosis, finally leading to the conclusion that this T-cell population is also heterogeneous in terms of its apoptotic potential. This review provides a comprehensive approach to the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population: we describe in detail its origins, molecular and functional characteristics, subsets, role in various diseases or conditions, associated with persistent antigenic stimulation.     

IL-4Ralpha signaling is important for CD8+ T cell cytotoxicity in the absence of CD4+ T cell help

Cytotoxic CD8(+) T cells are key mediators of viral clearance during primary infection through their production of IFN-gamma and lysis of virally infected cells. Comparatively, the cytokines IL-4 and IL-13 are typically associated with the development of Th2 immune responses against allergens and parasites, while their influence on cytotoxic CD8(+) T cell responses is controversial. We have investigated the roles of IL-4 and IL-13 in the development of CD8(+) T cell responses against influenza infection. We show that in the absence of either IL-4 or IL-13, CD8(+) T cells proliferated and a normal secondary cytotoxic response developed in vitro. In striking contrast, the absence of IL-4Ralpha resulted in impaired ex vivo proliferation and consequently no secondary CTL activity, whereas the in vivo response appeared normal. We show that the presence of CD4(+) T cell help, or the addition of exogenous IL-2 in vitro, restored the response. Taken together, this work reveals previously unrecognized in vivo redundancies between IL-4, IL-13 and IL-2 during immune responses against influenza virus.