Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival

Intraperitoneal peptide injection of TCR-transgenic mide or expression of antigen in hepatocytes leads to an accumulation in the liver of specific apoptotic CD8+ T cells expressing activation markers. To determine whether liver cells are capable of directly activating naive CD8+ T cells, we have studied the ability of purified hepatocytes to activate TCR-transgenic CD8+ T cells in vitro. We show that hepatocytes which do not express CD80 and CD86 co-stimulatory molecules are able to induce activation and effective proliferation of specific naive CD8+ T cells in the absence of exogenously added cytokines, a property only shared by professional antigen-presenting cells (APC). Specific T cell proliferation induced by hepatocytes was comparable in magnitude to that seen in response to dendritic cells and was independent of CD4+ T cell help or bystander professional APC co-stimulation. During the first 3 days, the same number of divisions was observed in co-cultures of CD8+ T cells with either hepatocytes or splenocytes. Both APC populations induced expression of early T cell activation markers and specific cytotoxic T lymphocyte (CTL) activity. However, in contrast to T cells activated by splenocytes, T cells activated by hepatocytes lost their cytolytic function after 3 days of co-culture. This correlated with death of activated T cells, suggesting that despite efficient activation, proliferation and transient CTL function, T cells activated by hepatocytes did not survive. Death could be prevented by adding antigen-expressing splenocytes or exogenous IL-2 to the co-culture, indicating that hepatocytes are not involved in direct killing of CD8+ T cells but rather fail to promote survival. Dying cells acquired a CD8low TCRlow B220+ phenotype similar to the one described for apoptotic intrahepatic T cells, suggesting an alternative model to account for the origin of these cells in the liver. The importance of these findings for the understanding of peripheral tolerance and the ability of liver grafts to be accepted is discussed.     

Activation of peripheral CD8+ T lymphocytes via CD28 plus CD2: Evidence for IL-2 gene transcription mediated by CD28 activation

It is well established that peripheral CD8+ and CD4+ T cells display different requirements for in vitro activation by mitogenic mAb. Most CD4+ T cells can be activated by anti-CD3 or mitogenic combinations of anti-CD2. In contrast, CD8+ T cells display minimal responses to CD3 activation, and no proliferation is observed via CD2 activation. Purified peripheral blood CD8+ T cells, stringently depleted of APC, have been studied for their capacity to respond to mAb directed against CD3, CD2 and CD28, used alone or in combination. It is demonstrated that proliferation can be induced by co-stimulation of CD2 and CD28. This does not require autologous APC. CD8+ T cells can also be activated by the combination of anti-CD3 plus anti-CD28 in the presence of APC, but only minimal cell proliferation is obtained in the absence of APC. The response via CD2 plus CD28 is IL-2-dependent, as demonstrated by the ability of mAb against the IL-2 receptor to block proliferation, and is almost completely inhibited by cyclosporine A (CsA). These results suggest that the signal generated by stimulation of CD28 in combination with CD2 differs from that seen with CD28 activation combined with either PMA or CD3. Induction of IL-2 gene activation in CD8+, CD28+ peripheral T cells may therefore require additional "second signals", which are not necessary for activation of CD4+ cells. One such signal might be the interaction between CD28 and its natural ligand.     

CD8+ T-cells suppress antigen-specific and allogeneic CD4+ T-cell responses to herpes simplex virus type 2-infected human dendritic cells

In this study we show that human dendritic cells (DC), productively infected with herpes simplex virus type 2 (HSV-2), activate CD8+ T cells that suppress antigen-specific and alloreactive CD4+ T cell expansion. Addition of CD8+ T cells to cultures of DC and CD4+ T cells blocked CD4+ T-cell proliferation in response to HSV-2-infected but not to uninfected DC. The effect was independent of prior HSV exposure or cognate MHC class I-restricted CD8-DC recognition as it was induced in CD8+ T cells from HSV-2-seronegative individuals and in mixed lymphocyte reactions using allogeneic DC. Both CD8+ CD25+ and CD8+ CD25- cells were shown to have suppressive capacities. The blood-derived CD25+ CD8+ T cells did not express Foxp3 mRNA but had a bona fide antiproliferative capacity in response to both uninfected and HSV-2-infected DC, whereas the CD25-CD8+ T cells were selectively activated to become antiproliferative by HSV-2-infected DC. These data imply that HSV infection of DC could modulate the immune response by activating CD8+ T cells.     

CD8 lethargy in the absence of CD4 help

CD4 T cell help was proposed to have a pivotal role in orienting CD8 T cell responses to antigen stimulation. By activating antigen-presenting cells (APC), CD4 cells would induce their expression of costimulatory molecules, the "signal two" required to induce full CD8 activation, preventing CD8 tolerance. Recent data on this subject is contradictory, as the absence of help did not always result in CD8 tolerance. These differences were attributed either to the presence of residual CD4 help or, respectively to the type of antigen stimulation, the peptide affinity, the CTL frequencies, and/or the strength of the response. We therefore reassessed the role of CD4 help in CD8 responses using a system where CD4 cells are absent and APC not activated. This system can be manipulated to induce CD8 tolerance (at high antigen concentrations) or CD8 memory (at low antigen concentrations). We found that the presence of CD4 help did not prevent tolerance induction. On the other hand, the absence of CD4 help did not induce CD8 tolerance, but rather led to differentiation stage intermediate between naive/memory/tolerant cells that we call "lethargy". These findings indicate that role of CD4 help in CD8 responses does not follow a simple on-off rule, as previously suggested. They also reveal that the "tolerance versus memory" dichotomy fails to account for all possible states/properties of antigen-experienced CD8 cells. Depending on the priming conditions, other intermediate stages of differentiation may occur.     

CpG DNA inhibits CD4+CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells

Toll-like receptor (TLR) ligands are notable for their ability to induce APC maturation, which in turn facilitates optimal T cell mediated immune responses. Toll-like receptor ligands, such as CpG DNA, can also modulate immune responses by blocking the suppressive effects of CD4+CD25+ regulatory T cells (Tregs). Recently, we have demonstrated that CpG DNA, in addition to its actions on APCs and Tregs, can provide direct costimulatory signals to CD4+CD25- T cells. Here we show that this costimulatory effect is sufficient to abrogate suppression by Tregs. These data indicate a previously undefined role for TLR ligands in directly modulating CD4+ T cell responses.     

Proliferation of human CD4+45R+ and CD4+45R- T helper cells is promoted by both IL-2 and IL-4 while interferon-gamma production is restricted to IL-2 activated CD4+45R- T cells

Recombinant IL-2 (rIL-2) and IL-4 (rIL-4) promote proliferation of human CD4+ T cells activated in the presence of PHA, TPA or OKT-3 monoclonal antibody (MAb), whereas the production of interferon-gamma (IFN) can be induced only by rIL-2. rIL-4 induced strong proliferative responses both in accessory cell independent assays and in the presence of autologous monocytes, but has failed to induce IFN production in any of these systems. The ability of rIL-2 to induce IFN production was strongly enhanced by the addition of monocytes, although a similar proliferative response was recorded in the absence or presence of monocytes. The MAb anti-Tac inhibited the proliferative response and the production of IFN by CD4+ T cells activated in the presence of rIL-2, whereas the proliferative response to rIL-4 was unaffected. CD4+45R+ and CD4+45R- T helper cell subsets proliferated in response to both IL-2 and IL-4. A kinetic analysis demonstrated that the production of IFN throughout a five day activation period was restricted to stimulation of CD4+45R- T cells with rIL-2. This report clearly demonstrates a dissociation of IFN production and T cell proliferation in man. While proliferation can be induced by both IL-2 and IL-4 in both the helper T cell subsets studied, IFN production was induced only in the CD4+45R- subsets and only in response to IL-2.     

Similar co-stimulation requirements of CD4+ and CD8+ primary T helper cells: role of IL-1 and IL-6 in inducing IL-2 secretion and subsequent proliferation.

Primary murine CD4+ and CD8+ T helper (Th) cells provide help for various immune responses by secreting lymphokines which activate effector cells. The purpose of the present study was to investigate the co-stimulatory signals that, together with T cell receptor (TCR) cross-linking, induce phenotypically distinct primary Th cells to secrete IL-2 and proliferate. We isolated highly purified populations of primary CD4+ or CD8+ T cells and stimulated them in vitro with platebound anti-CD3 mAb. TCR cross-linking by anti-CD3 mAb induced both IL-2 receptor expression and responsiveness to exogenous IL-2, but was not sufficient to induce either IL-2 secretion or T cell proliferation. Rather, for both CD4+ and CD8+ primary Th cells, IL-2 secretion and proliferation required both TCR cross-linking and antigen presenting cell (APC)-derived co-stimulatory signals. Based on G-10 adherence and sensitivity to gamma-irradiation, the APC populations able to induce primary CD4+ Th cells and primary CD8+ Th cells to secrete IL-2 were indistinguishable. In addition, we found that either IL-1 or IL-6 could replace the requirement for APC-derived co-stimulatory signals for IL-2 secretion and proliferation by both primary CD4+ Th cells and primary CD8+ Th cells. Thus, the present study has examined and compared the co-stimulatory requirements of rigorously purified subsets of IL-2-secreting primary CD4+ and primary CD8+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Induction of antigen-specific CD8+ cytolytic T cells by the exogenous bacterial antigen streptolysin O in rhesus monkeys.

We have characterized the T cell responses induced by streptolysin O (SLO), a sulfhydryl-activated hemolysin secreted by streptococci, by applying long-term in vitro culture and cloning rhesus monkey (Macaca mulatta) T cells. T cell lines specific for SLO were obtained from three rhesus monkeys. These T cell lines required autologous antigen-presenting cells (APC) to proliferate in response to SLO and did not respond to purified protein derivative. Phenotypic analysis showed that the cells from two of three SLO-specific T cell lines were more than 85% CD3+CD4-CD8+ after prolonged in vitro culture. The rh 1842 CD8+ T cell line proliferative response to SLO was inhibited by the addition of anti-major histocompatibility complex (MHC) class I and anti-CD8 but not of anti-MHC class II and anti-CD4 monoclonal antibody (mAb). This cell line was able to lyse P815 target cells in the presence of anti-CD3 mAb and did not show natural killer activity. Moreover, specific lysis of autologous but not allogeneic non-rosetting E- cell targets pulsed with SLO was observed. Such lysis was inhibited by the addition of anti-MHC class I mAb. In the attempt to identify the restriction elements involved in SLO presentation APC from six unrelated rhesus monkeys and three humans were used. A CD4+ rh 1842 T cell clone responded when SLO was presented by one of six, and a CD8+ rh 1842 T cell clone by four of six rhesus monkeys APC. Both CD4+ and CD8+ T cell clones did not respond when SLO was presented by human APC. However, both clones responded when APC from all donors were used in conjunction with anti-CD3 mb. Furthermore, SLO required active processing to be presented to CD4+ and CD8+ T cell clones as glutaraldehyde fixation of APC before but not after antigen pulsing inhibited T cell proliferation. The SLO-specific CD8+ cytolytic T cells described here could play a role in the regulation of the immune response occurring during streptococcal infections and/or could participate in the pathogenesis of poststreptococcal nonsuppurative sequelae.     

Hodgkin's reed-sternberg cell line (KM-H2) promotes a bidirectional differentiation of CD4+CD25+Foxp3+ T cells and CD4+ cytotoxic T lymphocytes from CD4+ naive T cells

A recent report revealed that a large population of Hodgkin's lymphoma-infiltrating lymphocytes (HLILs) consisted of regulatory T cells. In this study, we cocultured CD4+ naive T cells with KM-H2, which was established as a Hodgkin's Reed-Sternberg cell line, to clarify their ability to induce CD25+ Forkhead box P3+ (Foxp3+) T cells. The characteristic analyses of T cells cocultured with KM-H2 revealed the presence of CD4+CD25+ T cells. They expressed CTLA-4, glucocorticoid-induced TNFR family-related gene, and Foxp3 and could produce large amounts of IL-10. Conversely, KM-H2 also generated CD4+ CTLs, which expressed Granzyme B and T cell intracellular antigen-1 in addition to Foxp3+ T cells. They exhibit a strong cytotoxic effect against the parental KM-H2. In conclusion, KM-H2 promotes a bidirectional differentiation of CD4+ naive T cells toward Foxp3+ T cells and CD4+ CTLs. In addition to KM-H2, several cell lines that exhibit the APC function were able to generate Foxp3+ T cells and CD4+ CTLs. Conversely, the APC nonfunctioning cell lines examined did not induce both types of cells. Our findings suggest that the APC function of tumor cells is essential for the differentiation of CD4+ naive T cells into CD25+Foxp3+ T cells and CD4+ CTLs and at least partly explains the predominance of CD25+Foxp3+ T cells in HLILs and their contribution to a better prognosis. Therefore, in APC-functioning tumors, including classical Hodgkin lymphomas, which generate Foxp3+ T cells and CD4+ CTLs, these T cell repertories play a beneficial role synergistically in disease stability.     

Disproportionate recruitment of CD8+ T cells into the central nervous system by professional antigen-presenting cells

Inappropriate immune responses, thought to exacerbate or even to initiate several types of central nervous system (CNS) neuropathology, could arise from failures by either the CNS or the immune system. The extent that the inappropriate appearance of antigen-presenting cell (APC) function contributes to CNS inflammation and pathology is still under debate. Therefore, we characterized the response initiated when professional APCs (dendritic cells) presenting non-CNS antigens were injected into the CNS. These dendritic cells expressed numerous T-cell chemokines, but only in the presence of antigen did leukocytes accumulate in the ventricles, meninges, sub-arachnoid spaces, and injection site. Within the CNS parenchyma, the injected dendritic cells migrated preferentially into the white matter tracts, yet only a small percentage of the recruited leukocytes entered the CNS parenchyma, and then only in the white matter tracts. Although T-cell recruitment was antigen specific and thus mediated by CD4+ T cells in the models used here, CD8+ T cells accumulated in numbers equal to or greater than that of CD4+ T cells. Few of the recruited T cells expressed activation markers (CD25 and VLA-4), and those that did were primarily in the meninges, injection site, ventricles, and perivascular spaces but not in the parenchyma. These results indicate that 1) the CNS modulates the cellular composition and activation states of responding T-cell populations and that 2) myelin-restricted inflammation need not be initiated by a myelin-specific antigen.     

Stimulation with dendritic cells decreases or obviates the CD4+ helper cell requirement in cytotoxic T lymphocyte responses

We investigated the need for CD4+ helper T (Th) cells in the induction of murine cytotoxic T lymphocyte (Tc) responses across minor or major histocompatibility (MHC) antigenic differences with either normal spleen cells (NSC) or purified dendritic cells (DC) as antigen-presenting cells (APC). Generation of a secondary in vitro class II MHC-specific Tc response was totally CD4+ Th cell-dependent with both types of APC. Likewise, male antigen (H-Y)-primed class II mutant bm12 T cells, which do not respond to H-Y presented on NSC, do respond to H-Y presented on DC in a completely CD4+ Th cell-dependent fashion. All other Tc responses, including primary anti-class I MHC, primary anti-class I + II MHC plus anti-minor H, and secondary C57BL/6 (B6) anti-H-Y, although not completely CD4+ Th cell dependent, were greatly augmented in the presence of CD4+ Th cells, but only with NSC as APC. In contrast, with DC as APC these responses were entirely or largely CD4+ Th cell independent. Similarly, H-Y primed class I MHC mutant bm14 T cells, which do not respond to H-Y presented on NSC, do respond to H-Y presented on DC in a completely CD4+ Th cell-independent fashion. The combined results indicate that DC can directly present class I MHC alloantigen or class I MHC plus nominal antigen (e.g. minor H) to CD8+ cells and generate a Tc response by these cells without the requirement for CD4+ Th cells.     

CD4-mediated and CD8-mediated cytotoxic and proliferative immune responses to Toxoplasma gondii in seropositive humans.

Both CD4+ and CD8+ cytotoxic T lymphocytes (CTL) are part of the human immune response to Toxoplasma gondii infection. To further our understanding of Toxoplasma immunity, we investigated factors influencing stimulation of CD4+ or CD8+ human T. gondii-specific immune cells. Both antigen-pulsed and Toxoplasma-infected antigen-presenting cells (APC) induced cell proliferation. Toxoplasma-infected APC elicited strong proliferation of CD4+ cells, but little or no proliferation of CD8+ cells, unless high antigen loads were used. Toxoplasma-infected APC stimulated specific cytotoxicity poorly or not at all, owing to death of stimulated cultures, whereas antigen-pulsed APC strongly elicited specific cytotoxicity. Cytotoxicity elicited by either type of APC resided exclusively in CD4+ T cells in polyclonal cultures. Thus, Toxoplasma-infected APC elicited stronger CD4-mediated than CD8-mediated cell proliferation and generated CD4+ CTL more readily than CD8+ CTL. Nonetheless, specific CD8+ memory cells were demonstrated, and rare CD8+ Toxoplasma-specific CTL were subcloned. Fixed Toxoplasma-infected APC (which induce CD8+ CTL) also elicited cell proliferation, but polyclonal cultures stimulated with these infected APC did not die. Unfixed Toxoplasma-infected APC strongly inhibited phytohemagglutinin-induced cell proliferation, whereas fixed APC did not. These data suggested that infected APC were inhibitory or lethal to some immune cells. Further investigations into interactions between immune cells and Toxoplasma-infected cells likely will help elucidate factors involved in the immunopathogenesis of Toxoplasma infection. As other intracellular parasites, including Plasmodium spp. and Leishmania spp., also elicit CD4+ CTL, such work may help establish paradigms governing immunity to intracellular parasites.     

Human keratinocyte induction of rapid effector function in antigen-specific memory CD4+ and CD8+ T cells

The ability of human keratinocytes to present antigen to T cells is controversial and, indeed, it has been suggested that keratinocytes may promote T cell hyporesponsiveness. Furthermore, it is unclear whether keratinocytes can process antigen prior to MHC class I and class II presentation. We tested the ability of keratinocytes to induce functional responses in epitope-specific CD4+ and CD8+ memory T cells using peptides, protein and recombinant expression vectors as sources of antigen. Keratinocytes were able to efficiently process and present protein antigen to CD4+ T cells, resulting in cytokine secretion (Th1 and Th2). This interaction was dependent on keratinocyte expression of HLA class II and ICAM-1, which could be induced by IFN-gamma. In addition, keratinocytes could present virally encoded or exogenous peptide to CD8+ T cells, resulting in T cell cytokine production and target cell lysis. Finally, T cell lines grown using keratinocytes as stimulators showed no loss of function. These findings demonstrate that keratinocytes are able to efficiently process and present antigen to CD4+ and CD8+ memory T cells and induce functional responses. The findings have broad implications for the pathogenesis of cutaneous disease and for transcutaneous drug or vaccine delivery.     

Ex vivo induction of viral antigen-specific CD8 T cell responses using mRNA-electroporated CD40-activated B cells

Cell-based immunotherapy, in which antigen-loaded antigen-presenting cells (APC) are used to elicit T cell responses, has become part of the search for alternative cancer and infectious disease treatments. Here, we report on the feasibility of using mRNA-electroporated CD40-activated B cells (CD40-B cells) as alternative APC for the ex vivo induction of antigen-specific CD8(+) T cell responses. The potential of CD40-B cells as APC is reflected in their phenotypic analysis, showing a polyclonal, strongly activated B cell population with high expression of MHC and co-stimulatory molecules. Flow cytometric analysis of EGFP expression 24 h after EGFP mRNA-electroporation showed that CD40-B cells can be RNA transfected with high gene transfer efficiency. No difference in transfection efficiency or postelectroporation viability was observed between CD40-B cells and monocyte-derived dendritic cells (DC). Our first series of experiments show clearly that peptide-pulsed CD40-B cells are able to (re)activate both CD8+ and CD4(+) T cells against influenza and cytomegalovirus (CMV) antigens. To demonstrate the ability of viral antigen mRNA-electroporated CD40-B cells to induce virus-specific CD8+ T cell responses, these antigen-loaded cells were co-cultured in vitro with autologous peripheral blood mononuclear cells (PBMC) for 7 days followed by analysis of T cell antigen-specificity. These experiments show that CD40-B cells electroporated with influenza M1 mRNA or with CMV pp65 mRNA are able to activate antigen-specific interferon (IFN)-gamma-producing CD8(+) T cells. These findings demonstrate that mRNA-electroporated CD40-B cells can be used as alternative APC for the induction of antigen-specific (memory) CD8(+) T cell responses, which might overcome some of the drawbacks inherent to DC immunotherapy protocols.     

IL-4 deficiency does not impair the ability of dendritic cells to initiate CD4+ and CD8+ T cell responses in vivo

Several reports have described a role of IL-4 in dendritic cell function. We have examined the number and phenotype of dendritic cells from C57Bl/6 wild-type and IL-4-/- mice, and compared their ability to induce T cell immune responses in vivo and in vitro. We observed that the number of dendritic cells in the spleens and lymph nodes of IL-4-/- mice is comparable to the number found in wild-type mice. In addition, the expression of maturation markers such as MHC II, CD40, CD80 and CD86, and of differentiation markers such as CD4, CD8 and CD11b, was also comparable in the two populations. Splenic wild-type and IL-4-/- dendritic cells were both able to present antigen to T cell receptor transgenic CD4+ or CD8+ T cells in culture. When pulsed with antigen in vitro and then injected subcutaneously into C57BL/6 host mice, both populations of dendritic cells were able to induce the division of T cell receptor transgenic CD4+ or CD8+ T cells in vivo. This was the case regardless of whether the antigen used in these experiments was a low or a high affinity T cell receptor ligand. Similarly, both populations of dendritic cells were able to activate antigen-specific cytotoxic T cell responses and initiate tumor-protective immune responses in vivo. We conclude that IL-4-/- and wild-type dendritic cells have a comparable ability to initiate T cell immune responses when in an IL-4-sufficient environment.     

The central nervous system environment controls effector CD4+ T cell cytokine profile in experimental allergic encephalomyelitis

In experimental allergic encephalomyelitis (EAE), CD4⁺ T cells infiltrate the central nervous system (CNS). We derived CD4⁺ T cell lines from SJL/J mice that were specific for encephalitogenic myelin basic protein (MBP) peptides and produced both Th1 and Th2 cytokines. These lines transferred EAE to naive mice. Peptide-specific cells re-isolated from the CNS only produced Th1 cytokines, whereas T cells in the lymph nodes produced both Th1 and Th2 cytokines. Mononuclear cells isolated from the CNS, the majority of which were microglia, presented antigen to and stimulated MBP-specific T cell lines in vitro. Although CNS antigen-presenting cells (APC) supported increased production of interferon (IFN)-γ mRNA by these T cells, there was no increase in the interleukin (IL)-4 signal, whereas splenic APC induced increases in both IFN-γ and IL-4. mRNA for IL-12 (p40 subunit) was up-regulated in both infiltrating macrophages and resident microglia from mice with EAE. We have thus shown that a Th1 cytokine bias within the CNS can be induced by CNS APC, and that IL-12 is up-regulated in microglial cells within the CNS of mice with EAE. Microglia may therefore control Th1 cytokine responses within the CNS.     

B cells can prime naive CD4+ T cells in vivo in the absence of other professional antigen-presenting cells in a CD154-CD40-dependent manner

The role of B cells as APC is well established. However, their ability to prime naive T cells in vivo has been difficult to examine because of the presence of dendritic cells. The current studies were undertaken to examine this issue in a model of adoptive transfer of antigen-specific B cells and T cells into histoincompatible Rag2(-/-) mice. By means of this system, we were able to demonstrate that antigen-specific B cells are competent APC for naive CD4(+) T cells specific for the same antigen. In vivo antigen presentation resulted in expansion of both CD4(+) T cells and B cells. The antigen-presenting function of the transferred B cells was dependent on the CD154-CD40 interaction, as transfer of CD154-deficient antigen-specific CD4(+) T cells or CD40-deficient B cells failed to induce T and B cell expansion in response to immunization. These results indicate that antigen-specific B cells have the capacity to induce primary T cell responses in the absence of other competent APC.     

CD4+ and CD8+ T cell responses in Helicobacter pylori-infected individuals

In order to characterize T cell responses in human Helicobacter pylori infection, we have examined proliferative responses and cytokine production by CD4+ and CD8+ T cells isolated from duodenal ulcer patients and asymptomatic H. pylori carriers, after activation with some H. pylori antigens that may be important in disease development. For control purposes, T cells from uninfected volunteers were also examined. The different H. pylori antigens induced only modest proliferative responses in circulating CD4+ and CD8+ T cells from both H. pylori-infected and uninfected individuals. However, circulating T cells from H. pylori-infected subjects produced larger amounts of interferon-gamma (IFN-gamma) in response to the Helicobacter antigens than did T cells from uninfected volunteers. Furthermore, CD8+ T cells produced larger amounts of IFN-gamma than did CD4+ T cells, on a per cell basis. Most IFN-gamma-producing cells from both infected and uninfected volunteers appeared to be naive T cells expressing CD45RA. Increased production of IL-4 and IL-5 was, on the other hand, only seen in a few instances after stimulation of isolated CD4+ and CD8+ T cells. Stimulation of freshly isolated gastric T cells with the different H. pylori antigens did not result in increased proliferation or cytokine production. In conclusion, our results show that several different purified H. pylori antigens induce production of IFN-gamma, preferentially by CD8+ cells. Therefore, they suggest that IFN-gamma-secreting CD8+ cells contribute significantly to the cytokine response induced by H. pylori infection.     

Differential roles for CXCR3 in CD4+ and CD8+ T cell trafficking following viral infection of the CNS

Lymphocyte infiltration into the central nervous system (CNS) following viral infection represents an important component of host defense and is required for control of viral replication. However, the mechanisms governing inflammation in response to viral infection of the CNS are not well understood. Following intracranial (i.c.) infection of susceptible mice with mouse hepatitis virus (MHV), mice develop an acute encephalomyelitis followed by a chronic demyelinating disease. The CXC chemokine ligand 10 (CXCL10) is expressed following MHV infection and signals T cells to migrate into the CNS. The functional contribution of the CXCL10 receptor CXCR3 in host defense and disease in response to MHV infection was evaluated. The majority of CD4+ and CD8+ T cells infiltrating the CNS following MHV infection express CXCR3. Administration of anti-CXCR3 antibody reduced CD4+ T cell infiltration (p相似文献