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1.
Rapid disappearance of antiviral CTL after transfusion into persistently infected individuals is a serious limitation of adoptive immunotherapy protocols. In the mouse model of persistent infection with lymphocytic choriomeningitis virus (LCMV) naive or immune virus-specific donor CD8+ T cells are exhausted after transfusion into carrier recipients with similar kinetics. Here we show that cotransfusion of immune CD4+ T cells prevents exhaustion of immune CD8+ T cells. Interestingly, cotransfer of primed B cells also prevented CD8+ T cell exhaustion in carriers even in the absence of T helper cells. This effect required the presence of immune B cells as repetitive treatment with hyperimmune serum led to the generation of antibody escape mutants. A combination of primed CD4+ T cells and primed B cells enhanced antiviral effects and prevented exhaustion also of naive CD8+ T cells. One key factor for prevention of CD8+ T cell exhaustion was the antiviral effect of the cotransfused cells thus reducing the time that CD8+ T cells are confronted with a high systemic viral load. These findings have implications for improving adoptive immunotherapy for persistent human viral infections. 相似文献
2.
The requirements for the conversion of CD8+ memory T cells into effector class I major histocompatibility complex (MHC) Kd-restricted cytotoxic T (Tc) cells in vitro have been studied. Purified CD8+ splenocytes from influenza A/WSN-primed BALB/c (H-2d) mice stimulated with a synthetic nucleoprotein peptide 147-158 R156- (NPP) alone generated Tc cells specific for influenza virus-infected target cells. No additional requirements for accessory cells or their lymphokine products were necessary indicating that peptide antigen (Ag) in association with Kd was presented on CD8+ T cells. The evidence for presentation of NPP by CD8+ T cells was supported by the use of CD8+ memory T cells from semiallogeneic bone marrow radiation chimeras of P1----F1 type (H-2b----[H-2d x H-2b]F1). Memory CD8+ splenocytes from A/WSN-immune chimeras did not develop into secondary effector Tc cells as a result of a 4-day culture with NPP alone, however, were able to do so if NPP was presented by Kd-bearing Ag-presenting cells. In addition, these results exclude the possibility of direct recognition of free NPP molecules by the specific T cell receptor of CD8+ memory T cells. CD8+ memory splenocytes (H-2b) from chimeras were also able to develop into functionally active Tc cells as a result of presentation of Db-restricted synthetic peptide (NP 366-374) with a sequence derived from influenza virus nucleoprotein with high affinity for Db MHC class I molecules. Blockade of endogenously produced interleukin 2 (IL-2) activity by anti-IL-2 or anti-IL-2 receptor monoclonal antibody in the culture of CD8+ memory T cells during a 4-day NPP stimulation completely abolished Tc cell generation, indicating that the utilization of this lymphokine is absolutely required for the secondary Tc cell development. These findings demonstrate that CD8+ memory T cells per se are able to recognize the restimulating epitope as a result of its presentation by CD8+ T cells and develop into cytolytically active and highly specific Tc cells with no requirements for other cellular helper components or their lymphokine products. 相似文献
3.
Reduced lysis by CD8+ cytotoxic T cells in mixed lymphocyte reactions induced via CD4+ T cells exposed to chemically modified antigen presenting cells. 下载免费PDF全文
The resistance by T lymphocytes to activation by antigen (anergy) is well documented for CD4+ T-helper (Th) cells, although less is known about CD8+ cytotoxic T lymphocytes (CTL). One widely used method of inducing anergy of CD4+Th is presentation of antigen by ECDI (1-ethyl-3-(3-dimethylamino-propyl)carbodiimide)-fixed antigen-presenting cells (APCs). We report here that in murine mixed lymphocyte reactions (MLRs), a marked reduction in detected cytotoxicity (which is mediated predominantly by CD8+ CTL) occurs on day 7 if the bulk cultures are restimulated 2 days previously with ECDI-fixed allogeneic splenocytes. No differences were seen between untreated cultures on days 5 and 7, or on day 7 of cultures to which were added unfixed allogeneic splenocytes, fixed or unfixed syngeneic splenocytes, or 'third-party' allogeneic splenocytes, 2 days previously. The effect is not mediated directly on CD8+ cells, since MLRs depleted of CD4+ cells immediately prior to exposure to fixed allogeneic splenocytes fail to show reduced lysis. On the other hand, reduced lysis did occur if CD4+ cells, purified from the MLRs on day 4, were exposed to ECDI-fixed allogeneic splenocytes and then returned to MLRs previously depleted of CD4+ cells. Moreover the effect is overcome using exogenous interleukin-2 (IL-2). We propose that CD4+ cells, restimulated by a regimen shown previously to induce their anergy, can cause a reduction in CD(8+)-mediated cytotoxicity in MLRs. 相似文献
4.
Kolbaum J Tartz S Hartmann W Helm S Nagel A Heussler V Sebo P Fleischer B Jacobs T Breloer M 《European journal of immunology》2012,42(4):890-900
Malaria is still responsible for up to 1 million deaths per year worldwide, highlighting the need for protective malaria vaccines. Helminth infections that are prevalent in malaria endemic areas can modulate immune responses of the host. Here we show that Strongy-Ioides ratti, a gut-dwelling nematode that causes transient infections, did not change the efficacy of vaccination against Plasmodium berghei. An ongoing infection with Litomosoides sigmodontis, a tissue-dwelling filaria that induces chronic infections in BALB/c mice, significantly interfered with vaccination efficacy. The induction of P. berghei circumspor-ozoite protein (CSP)-specific CD8(+) T cells, achieved by a single immunization with a CSP fusion protein, was diminished in L. sigmodontis-infected mice. This modulation was reflected by reduced frequencies of CSP-specific CD8(+) T cells, reduced CSP-specific IFN-y and TNF-a production, reduced CSP-specific cytotoxicity, and reduced protection against P. berghei challenge infection. Implementation of a more potent vaccine regime, by first priming with CSP-expressing recombinant live Salmonella prior to CSP fusion protein immunization, restored induction of CSP-specific CD8(+) T cells and conferred almost sterile immunity to P. berghei challenge infection also in L. sigmodontis-infected mice. In summary, we show that appropriate vaccination regimes can overcome helminth-induced interference with vaccination efficacy. 相似文献
5.
Heleen Kuiper Miranda Brouwer Mark de Boer Paul Parren Ren A. W. Van Lier 《European journal of immunology》1994,24(9):1956-1960
Activation of naive CD4+ T cells is essential for the induction of primary immune responses. However, this subset is less responsive to signaling via T cell receptor/CD3 (TcR/CD3) complex than memory CD4+ cells. For mitogenic activation of T cells, in addition to triggering of the TcR/CD3 complex, costimulatory signals are required that can be generated by surface structures present on the antigen-presenting cells. We investigated here whether differences in responsiveness to TcR/CD3 stimulation of naive and memory cells can be overcome by the costimulatory pathway B7/CD28. Using a B7-dependent system we show that even in the presence of optimal CD28 costimulation, CD4+ naive cells still have more stringent TcR/CD3 activation requirements than memory cells. Furthermore, titration of the B7 signal revealed that for activation of naive CD4+ cells a higher level of cross-linking of CD28 molecules is required than for memory cells. Thus, our results show that at least two signals are required for activation of both CD4+ memory and naive cells, but that for activation of naive cells higher cross-linking of both CD3 and CD28 molecules is necessary. 相似文献
6.
Requirement of CD4+ T cells and antigen-presenting cells for primary in vitro generation of CD8+ cytotoxic T cells against Ld-binding self-peptide p2Ca. 下载免费PDF全文
We investigated the cellular requirement for primary in vitro generation of cytotoxic T-lymphocytes (CTL) in BALB/c spleen cells against Ld-binding self-peptide p2Ca. Depletion of CD4+ T-cells in vitro by pretreatment with anti-CD4 monoclonal antibody (mAb) and complement or in vivo by administration of anti-CD4 mAb abrogated generation of CTL. Depletion of adherent cells by passing spleen cells through a nylon wool (NW) column also abrogated generation of CTL. Addition of peritoneal exudate cells (PEC) to spleen cells passed through the NW column restored CTL generation. These findings indicate that both CD4+ T-cells and antigen-presenting cells (APC) were necessary for CTL generation. Treatment of PEC with paraformaldehyde (PFA), but not mitomycin-C (MMC) abrogated their ability to restore CTL generation when mixed with spleen cells from the NW column, suggesting that an endocytic pathway could be involved in presentation of p2Ca on APC. 相似文献
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We demonstrate that pretreatment of primary CD4+, but not CD8+ T cells with anti-CD45 inhibits activation signals induced through the T cell receptor for antigen (TCRαβ). Specifically, anti-TCRαβ-mediated tyrosine phosphorylation of phospholipase C-γ1 is inhibited, and this in turn correlates with the inhibition of subsequent Ca2+ mobilization and DNA synthesis. In marked contrast, none of these activation parameters are affected by anti-CD45 in CD8+ T cells. Perturbation of TCRαβ signalling in CD4+ cells is observed in conditions which do not detectably affect the level of CD45 expression, or its membrane distribution. Further, changes in the intrinsic phosphatase activity of CD45 are not detectable. While anti-CD45 ablates TCRαβ signalling, anti-CD3?-mediated activation is unaffected. This suggests that elements of the antigen receptor complex can be functionally uncoupled, and indicates that the requirements for CD45 in signalling through these two elements are different. The results demonstrate that the involvement of CD45 in coupling TCRαβ to second messenger-generating pathways is under distinct physical and/or functional constraints in primary CD4+ and CD8+ T cells. 相似文献
9.
Haile Y Pasychniyk D Turner D Bleackley RC Giuliani F 《Journal of leukocyte biology》2011,89(6):927-934
MS lesions are characterized by destruction of myelin and significant neuronal and axonal loss. Preliminary studies with the use of T(regs) in the mouse model of MS have been extremely encouraging. However, recent studies with human cells have shown the presence of different subpopulations of T cells within the CD4(+)CD25(+)Foxp3(+) T cell phenotype, some of which do not have regulatory functions. These findings suggest a potential difference between mouse and human in the regulatory phenotype. Here, we show that human activated CD4(+)CD25(+)Foxp3(+) T cells are neurotoxic in vitro. These cells expressed high levels of the cytotoxic molecule GrB and had no suppressive effect. On the contrary, they produced IFN-γ and low IL-17, suggesting a shift toward a T(H)1 phenotype. Thus, our data confirm the presence of a nonregulatory cytotoxic subpopulation within the human CD4(+)CD25(+)Foxp3(+) T cells and suggest further studies on the human regulatory phenotype prior to any potential therapeutic application. 相似文献
10.
Reinhold Schirmbeck Jens Zerrahn Andreas Kuhrber Evelyn Kury Wolfgang Deppert Jrg Reimann 《European journal of immunology》1992,22(3):759-766
C57BL/6 (B6) mice (H-2b) were immunized with the large tumor antigen (T Ag) of simian virus 40 (SV40). Intraperitoneal or subcutaneous sensitization with soluble T Ag specifically primed cytotoxic lymphocyte precursors (CTLp). T Ag-specific cytotoxic T lymphocytes (CTL) were detected in a cytotoxicity assay after specific in vitro restimulation of effector cell populations from mice immunized with 2-10 micrograms purified, soluble T Ag and boosted with an injection of 2 micrograms T Ag 2-4 weeks after priming. Cells used for in vitro restimulation and as targets in cytotoxicity assays were syngeneic (B6-derived) RBL5 lymphoma cells expressing SV40 T Ag after transfection with a T Ag-encoding expression vector. Effector cells of this response were H-2 class I-restricted CD3+ CD4-CD8+ CTL. The magnitude of the anti-T Ag CTL response of B6 mice stimulated by soluble virus protein was comparable to the anti-T Ag CTL response of SV40-infected B6 mice. Injections of denatured or native T Ag protein primed CTLp equally well, but immunization with an equal dose of antigen emulsified in incomplete Freund's adjuvants inefficiently stimulated CTLp. 相似文献
11.
Mautner J Pich D Nimmerjahn F Milosevic S Adhikary D Christoph H Witter K Bornkamm GW Hammerschmidt W Behrends U 《European journal of immunology》2004,34(9):2500-2509
The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is the only viral protein regularly expressed in EBV-associated malignancies. Immune recognition of EBNA1 by CD8+ T cells is prevented by an internal glycine-alanine repeat (GAr) which blocks proteasomal degradation. To test whether EBV-infected cells could be recognized by T helper cells, human CD4+ T cell clones specific for EBNA1 were isolated from latently EBV-infected individuals. These T cells, however, failed to recognize EBV-positive target cells. To investigate whether endogenous presentation of EBNA1 epitopes on MHC class II was prevented by the GAr domain, a mutant EBV strain with an EBNA1 lacking the GAr (EBNA1DeltaGA) was generated and used to establish an Epstein-Barr virus-immortalized lymphoblastoid B cell line (LCL). The EBNA1DeltaGA LCL were not recognized by the EBNA1-specific T cell clones either, indicating that the GAr domain does not mediate this effect. Immune recognition could be restored by overexpression of EBNA1, for which at least 60-fold higher levels of both EBNA1 or EBNA1DeltaGAr protein were required. These results demonstrate that EBNA1 evades direct recognition by CD4+ T helper cells, since its steady state level is below the threshold required for efficient presentation on MHC class II. These findings have important implications for the design of immunotherapeutic approaches to target EBV-positive malignancies. 相似文献
12.
Dominique Kaiserlian Karine Vidal Jean-Pierre Revillard 《European journal of immunology》1989,19(8):1513-1516
Highly purified mature epithelial cells (EC) from murine small intestinal villi (excluding Peyer's patch epithelium) were examined for their capacity to present foreign antigen to T cells. Cell suspensions composed of 99% Ia+T200- EC were able to present keyhole limpet hemocyanin to an antigen-specific class II-restricted L3T4+ T cell hybridoma, and stimulate interleukin 2 production. Antigen presentation by EC was inhibited by major histocompatibility complex class II-specific monoclonal antibodies. It is concluded that EC express functional class II molecules and may activate adjacent CD4+ T cells to induce lymphokine synthesis. 相似文献
13.
The relative contributions of different types of antigen presenting cells to T-cell activation, expansion and induction of effector functions are still not fully understood. In order to evaluate the roles of dendritic versus B cells during these phases of a CD4 T-cell response in vivo, we adoptively transferred major histocompatibility complex class II restricted, T-cell receptor-transgenic CD4+ T cells into transgenic mice expressing selectively the T-cell restricting class II molecules on either dendritic cells, B cells or both. Upon immunization with peptide antigen, we observed that dendritic cells were sufficient to induce activation, expansion, interleukin-2 production and germinal centre migration of antigen-specific T cells, independently of other antigen-presenting cells. In contrast, neither resting nor activated B cells had similar antigen-presenting capacities in vivo. However, in double transgenic mice where both B cells and dendritic cells were capable of presenting antigen, T cells showed increased proliferation, expansion and cytokine production in vivo. Moreover, higher antigen-specific CD4 T-cell numbers accumulated in germinal centres. Our data demonstrate that dendritic cells are sufficient to activate naive CD4 T cells in vivo, but B cells subsequently can enhance CD4 T-cell expansion further. 相似文献
14.
Patients with genital herpes have frequent viral reactivations. The repeated antigenic rechallenges can modulate the CD4+ memory T-cell repertoires during the course of infection. In this study, the CD4+ T-cell responses against the herpes simplex virus type 2 (HSV-2) tegument protein VP16 were studied in two HSV-2-infected subjects at two different time points that spanned a 5-year period. Although the VP16-specific T cells did exhibit variation of T-cell receptor Vbeta usages at the two time points, T cells that used identical Vbeta and CDR3 junction sequences were also observed at the two time points. These experiments demonstrate that the CD4+ T cells that are directed against HSV-2 VP16 protein in chronically infected individuals are oligoclonal and that T cells of specific clonotypes can be maintained throughout the course of the disease. 相似文献
15.
M Ebisawa D C Reason H Saito S Nakano K Seo K Kawamura Y Iikura 《Annals of allergy》1991,67(6):612-614
Neonatal human CD4+ T cells will co-express CD8 on their surface following short-term culture with interleukin 4 (IL-4). Adult T cells do not respond in this manner. In this study we examine this phenomenon as a function of age and determine that IL-4 responsiveness decreases with time to approach adult levels at about 2 years. This phenomenon may be relevant to the documented ability of neonatal CD4+ T cells to function as suppressors. 相似文献
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To examine heterogeneity in dendritic cell (DC) antigen presentation function, murine splenic DCs were separated into CD4+ and CD8+ populations and assessed for the ability to process and present particulate antigen to CD4+ and CD8+ T cells. CD4+ and CD8+ DCs both processed exogenous particulate antigen, but CD8+ DCs were much more efficient than CD4+ DCs for both major histocompatibility complex (MHC) class II antigen presentation and MHC class I cross-presentation. While antigen processing efficiency contributed to the superior antigen presentation function of CD8+ DCs, our studies also revealed an important contribution of CD24. CD8+ DCs were also more efficient than CD4+ DCs in inducing naïve T cells to acquire certain effector T-cell functions, for example generation of cytotoxic CD8+ T cells and interferon (IFN)-γ-producing CD4+ T cells. In summary, CD8+ DCs are particularly potent antigen-presenting cells that express critical costimulators and efficiently process exogenous antigen for presentation by both MHC class I and II molecules. 相似文献
18.
Stimulation with dendritic cells decreases or obviates the CD4+ helper cell requirement in cytotoxic T lymphocyte responses 总被引:3,自引:0,他引:3
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. 相似文献
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CD4+ T cells can exert different effector functions, which are partly distinguishable by the secretion of different cytokines, namely by either IFN-γ, IL-2 and lymphotoxins for Th1-like or IL-4, IL-5, IL-10 and IL-13 for Th2-like T cells. Th1-like T cells can exert cytotoxic functions, too. The cytokinetic phenotype of an activated T cell clone (TCC) is mainly influenced by the cytokinetic pattern of the microenvironment where it was activated. However, the interaction between certain adhesion molecules (i.e. CD28-CD80 and CD28-CD86) may also have an influence on the functionality of the reactive T cell. On the contrary, the requirements for the induction of CD4+ cytotoxic T cells (CD4+CTLs) are not well understood. We have focused this review on studies investigating the development of CD4+ T cells with cytotoxic effector functions. In particular, we discuss here whether the type of antigen-presenting cells (APCs) and the distinct expression of important adhesion molecules like CD80 and CD86 may influence the generation of CD4+ CTLs. Among a large panel of APCs only dendritic cells and TCCs are able to induce cytotoxicity. The level of CD80, but not of CD86, present on the APCs appears to be crucial for the induction of CD4+ CTLs. 相似文献