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1.
van Den Broek M Bachmann MF Köhler G Barner M Escher R Zinkernagel R Kopf M 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(1):371-378
Resistance or susceptibility to most infectious diseases is strongly determined by the balance of type 1 vs type 2 cytokines produced during infection. However, for viruses, this scheme may be applicable only to infections with some cytopathic viruses, where IFN-gamma is considered as mandatory for host defense with little if any participation of type 2 responses. We studied the role of signature Th1 (IL-12, IFN-gamma) and Th2 (IL-4, IL-10) cytokines for immune responses against vaccinia virus (VV). IL-12-/- mice were far more susceptible than IFN-gamma-/- mice, and primary CTL responses against VV were absent in IL-12-/- mice but remained intact in IFN-gamma-/- mice. Both CD4+ and CD8+ T cells from IL-12-/- mice were unimpaired in IFN-gamma production, although CD4+ T cells showed elevated Th2 cytokine responses. Virus replication was impaired in IL-4-/- mice and, even more strikingly, in IL-10-/- mice, which both produced elevated levels of the proinflammatory cytokines IL-1alpha and IL-6. Thus, IL-4 produced by Th2 cells and IL-10 produced by Th2 cells and probably also by macrophages counteract efficient anti-viral host defense. Surprisingly, NO production, which is considered as a major type 1 effector pathway inhibited by type 2 cytokines, appears to play a limited role against VV, because NO sythetase 2-deficient mice did not show increased viral replication. Thus, our results identify a new role for IL-12 in defense beyond the induction of IFN-gamma and show that IL-4 and IL-10 modulate host protective responses to VV. 相似文献
2.
A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses 总被引:21,自引:0,他引:21
CD4+ helper T (TH) cells play crucial roles in immune responses. Recently a novel subset of TH cells, termed THIL-17, TH 17 or inflammatory TH (THi), has been identified as critical mediators of tissue inflammation. These cells produce IL-17 (also called IL-17A) and IL-17F, two most homologous cytokines sharing similar regulations. Here we report that when overexpressed in 293T cells, IL-17 and IL-17F form not only homodimers but also heterodimers, which we name as IL-17A/F. Fully differentiated mouse THi cells also naturally secrete IL-17A/F as well as IL-17 and IL-17F homodimeric cytokines. Recombinant IL-17A/F protein exhibits intermediate levels of potency in inducing IL-6 and KC (CXCL 1) as compared to homodimeric cytokines. IL-17A/F regulation of IL-6 and KC expression is dependent on IL-17RA and TRAF6. Thus, IL-17A/F cytokine represents another mechanism whereby T cells regulate inflammatory responses and may serve as a novel target for treating various immune-mediated diseases. 相似文献
3.
Pertussis toxin by inducing IL-6 promotes the generation of IL-17-producing CD4 cells 总被引:4,自引:0,他引:4
Compelling evidence has now demonstrated that IL-17-producing CD4 cells (Th17) are a major contributor to autoimmune pathogenesis, whereas CD4+CD25+ T regulatory cells (Treg) play a major role in suppression of autoimmunity. Differentiation of proinflammatory Th17 and immunosuppressive Treg from naive CD4 cells is reciprocally related and contingent upon the cytokine environment. We and others have reported that in vivo administration of pertussis toxin (PTx) reduces the number and function of mouse Treg. In this study, we have shown that supernatants from PTx-treated mouse splenic cells, which contained IL-6 and other proinflammatory cytokines, but not PTx itself, overcame the inhibition of proliferation seen in cocultures of Treg and CD4+CD25- T effector cells. This stimulatory effect could be mimicked by individual inflammatory cytokines such as IL-1beta, IL-6, and TNF-alpha. The combination of these cytokines synergistically stimulated the proliferation of CD4+CD25- T effector cells despite the presence of Treg with a concomitant reduction in the percentage of FoxP3+ cells and generation of IL-17-expressing cells. PTx generated Th17 cells, while inhibiting the differentiation of FoxP+ cells, from naive CD4 cells when cocultured with bone marrow-derived dendritic cells from wild-type mice, but not from IL-6-/- mice. In vivo treatment with PTx induced IL-17-secreting cells in wild-type mice, but not in IL-6-/- mice. Thus, in addition to inhibiting the development of Treg, the immunoadjuvant activity of PTx can be attributable to the generation of IL-6-dependent IL-17-producing CD4 cells. 相似文献
4.
5.
Okamoto I Kohno K Tanimoto T Ikegami H Kurimoto M 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(6):3202-3211
We investigated the effects of IL-18 on the development of CD8+ effector T cells in DBA/2 anti-BDF1 whole spleen cell MLC and compared the results with those of IL-12. Addition of IL-18 to the MLC resulted in a twofold increase in CD8/CD4 ratios compared with the control cultures when cells were expanded in IL-2-containing medium following MLC. Purified CD8+ T cells recovered from the IL-18-stimulated MLC produced 20- to 30-fold more IFN-gamma after secondary stimulation with C57BL/6 spleen cells or anti-CD3 mAb, and exhibited strong allospecific CTL activity. Neither IL-18 nor IL-18-supplemented culture supernatants from DBA/2 anti-BDF1 MLC induced type I CD8+ effector T cells when purified CD8+ T cells were used as responder cells in primary MLC. Furthermore, CD4+ T cell depletion from the responder cells abrogated the IL-18-induced increase in secondary IFN-gamma production by CD8+ T cells, suggesting that IL-18-induced type I effector CD8+ T cell development was CD4+ T cell dependent. In marked contrast, adding IL-12 to primary MLC decreased CD8/CD4 ratios by 50% and suppressed secondary IFN-gamma production and CTL activity by CD8+ T cells regardless of concentration, whereas Th1 development was promoted by IL-12. Moreover, both IL-12 and IL-18 efficiently induced type I CD8+ effector T cells in C57BL/6 anti-BDF1 MLC. These findings show that IL-18 plays an important role in the generation of type I CD8+ effector T cells, and further suggest that functional maturation of CD8+ T cells is differentially regulated by IL-18 and IL-12. 相似文献
6.
Buch S Pinson D King CL Raghavan R Hou Y Li Z Adany I Hicks A Villinger F Kumar A Narayan O 《Cytokine》2001,13(5):295-304
HIV-1 is dual-tropic for CD4+ T lymphocytes and macrophages, but virus production in the macrophages becomes manifest only during late-stage infection, after CD4+ T cell functions are lost, and when opportunistic pathogens begin to flourish. In this study, the SHIV/macaque model of HIV pathogenesis was used to assess the role of cytokines in regulating virus replication in the two cell types. We injected complete Freund's adjuvant (CFA) intradermally into SHIV(KU)-infected macaques, and infused Schistosoma mansoni eggs into the liver and lungs of others. Tissues examined from these animals demonstrated that macrophages induced by CFA did not support viral replication while those induced by S. mansoni eggs had evidence of productive infection. RT-PCR analysis showed that both Th1 (IL-2 and IFN-gamma) and Th2 cytokines (IL-4 and IL-10) were present in the CFA lesions but only the Th2 cytokines were found in the S. mansoni lesions. Follow-up studies in macaque cell cultures showed that whereas IFN-gamma caused enhancement of virus replication in CD4+ T cells, it curtailed viral replication in infected macrophages. In contrast, IL-4 enhanced viral replication in infected macrophages. These studies strongly suggest that cytokines regulate the sequential phases of HIV replication in CD4 T cells and macrophages. 相似文献
7.
Kannan-Hayashi Y Okamura K Hattori S Kuwamura M Higuchi E Terayama H Moriyama M Mukamoto M Okada M Ohsugi Y Nakamura Y 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(6):4227-4234
To determine the role played by lymphocytes and cytokines in the growth of sympathetic neurons in vivo, the innervation and cytokine levels were examined in the spleens of SCID mice that lack T and B cells. Splenic noradrenaline, nerve growth factor (NGF), and IL-1beta levels were elevated in SCID mice. Immunohistochemical examination revealed that the density of tyrosine hydroxylase-positive (TH(+)) fibers of splenic central arteries in SCID mice was increased compared with wild-type C.B-17 mice, while SCID mice had significantly fewer TH(+) fibers in their periarteriolar lymphatic sheaths (PALS). Two weeks after SCID mice were injected with C.B-17 splenic T cells, their TH(+) fiber staining increased in the PALS. IL-3 levels increased significantly in SCID mice following T cell reconstitution, and the administration of anti-IL-3 Ab blocked the above T cell-induced increase in innervation in the PALS. Anti-IL-3 treatment also inhibited the regeneration of splenic sympathetic neurons in C.B-17 mice after they were chemically sympathetomized with 6-hydroxydopamine. Depletion of NK cells by anti-asialo GM1 promoted the splenic innervation in SCID mice, while there were no significant changes in the innervation between CD8(+) T cell-deficient beta(2)-microglobulin knockout mice and their wild type. Our results suggest that T cells (probably CD4(+) Th cells but not CD8(+) CTLs) play a role in regulating the sympathetic innervation of the spleen; this effect appeared to be mediated, at least in part, by IL-3. On the contrary, NK cells may exert an inhibitory effect on the sympathetic innervation. 相似文献
8.
The biology of IL-12: coordinating innate and adaptive immune responses 总被引:13,自引:0,他引:13
Cytokines play critical roles in regulating all aspects of immune responses, including lymphoid development, homeostasis, differentiation, tolerance and memory. Interleukin (IL)-12 is especially important because its expression during infection regulates innate responses and determines the type and duration of adaptive immune response. IL-12 induces interferon-gamma (IFN-gamma) production by NK, T cells, dendritic cells (DC), and macrophages. IL-12 also promotes the differentiation of na?ve CD4+ T cells into T helper 1 (Th1) cells that produce IFN-gamma and aid in cell-mediated immunity. As IL-12 is induced by microbial products and regulates the development of adaptive immune cells, IL-12 plays a central role in coordinating innate and adaptive immunity. IL-12 and the recently identified cytokines, IL-23 and IL-27, define a family of related cytokines that induce IFN-gamma production and promote T cell expansion and proliferation. 相似文献
9.
Won HY Lee JA Park ZS Song JS Kim HY Jang SM Yoo SE Rhee Y Hwang ES Bae MA 《PloS one》2011,6(3):e18168
Increasing evidence that decreased bone density and increased rates of bone fracture are associated with abnormal metabolic states such as hyperglycemia and insulin resistance indicates that diabetes is a risk factor for osteoporosis. In this study, we observed that TallyHo/JngJ (TH) mice, a polygenic model of type II diabetes, spontaneously developed bone deformities with osteoporotic features. Female and male TH mice significantly gained more body weight than control C57BL/6 mice upon aging. Interestingly, bone density was considerably decreased in male TH mice, which displayed hyperglycemia. The osteoblast-specific bone forming markers osteocalcin and osteoprotegerin were decreased in TH mice, whereas osteoclast-driven bone resorption markers such as IL-6 and RANKL were significantly elevated in the bone marrow and blood of TH mice. In addition, RANKL expression was prominently increased in CD4+ T cells of TH mice upon T cell receptor stimulation, which was in accordance with enhanced IL-17 production. IL-17 production in CD4+ T cells was directly promoted by treatment with leptin while IFN-γ production was not. Moreover, blockade of IFN-γ further increased RANKL expression and IL-17 production in TH-CD4+ T cells. In addition, the osteoporotic phenotype of TH mice was improved by treatment with alendronate. These results strongly indicate that increased leptin in TH mice may act in conjunction with IL-6 to preferentially stimulate IL-17 production in CD4+ T cells and induce RANKL-mediated osteoclastogenesis. Accordingly, we propose that TH mice could constitute a beneficial model for osteoporosis. 相似文献
10.
The phenotype and frequency of cells in normal human peripheral blood spontaneously secreting IL-2, IL-4, IL-6, IL-10, IFN and TNF-α ex vivo was determined using ELIspot assays. CD4+T cells were the dominant source of IL-2 and IL-4 while multiple cell types (primarily CD8+lymphocytes) produced IFN. Fewer than 0.05% of mononuclear cells were spontaneously secreting these T cell derived factors. By comparison, IL-6, IL-10 and TNF-α were produced by 0.7–20% of PBMC. The primary sources of the latter cytokines were CD14+macrophages/monocytes. A significant positive correlation was found in the frequency of cells secreting IL-6, IL-10 and TNF-α ex vivo, suggesting that the release of such factors was coordinately regulated. No such correlation was found among IL-2, IL-4 and IFN secreting cells, indicating that the production of predominantly T cell derived cytokines was regulated independently. 相似文献
11.
Chiarella AP Arruda C Pina A Costa TA Ferreira RC Calich VL 《Microbes and infection / Institut Pasteur》2007,9(9):1078-1088
Protective immunity in paracoccidioidomycosis (PCM) is believed to be mediated by cellular immunity, but the role of T cell subsets has never been investigated. The aim of this study was to characterize the function of CD4+ and CD8+ T cells in the immunity developed by susceptible, intermediate and resistant mice after P. brasiliensis infection. In susceptible mice, depletion of CD4+ T cells did not alter disease severity and anergy of cellular immunity but diminished antibody production. Anti-CD8 treatment led to increased fungal loads, but restored DTH reactivity. In resistant mice, both CD4+ and CD8+ T cells control fungal burdens and cytokines although only the former regulate DTH reactions and antibody production. In the intermediate strain, deficiency of whole T and CD8+ T cells but not of CD4+ T or B cells led to increased mortality rates. Thus, in pulmonary PCM: (a) irrespective of the host susceptibility pattern, fungal loads are mainly controlled by CD8+ T cells, whereas antibody production and DTH reactions are regulated by CD4+ T cells; (c) CD4+ T cells play a protective role in the resistant and intermediate mouse strains, whereas in susceptible mice they are deleted or anergic; (d) genetic resistance to PCM is associated with concomitant CD4+ and CD8+ T cell immunity secreting type 1 and type 2 cytokines. 相似文献
12.
Monokine production by human T cells; IL-1 alpha production restricted to memory T cells. 总被引:2,自引:0,他引:2
C van Kooten I Rensink D Pascual-Salcedo R van Oers L Aarden 《Journal of immunology (Baltimore, Md. : 1950)》1991,146(8):2654-2658
The production of cytokines is a key event of inflammation. In this report we demonstrate that normal human T cells are capable to produce IL-1 alpha, IL-6, and TNF-alpha, cytokines formerly considered to be monokines. This production was optimal after stimulation with a combination of anti-CD2, PMA, and anti-CD28. All three cytokines were produced in a bioactive form. Both naive (CD4+CD45RA+) and memory (CD4+CD45RO+) subsets of T cells were shown to produce similar amounts of IL-6 and TNF-alpha. In contrast the production of IL-1 alpha was found to be completely restricted to the CD4+CD45RO+ subset. The finding that T cells are such potent producers of these important mediators of the inflammatory response might be a key observation in the appreciation of the role of T cells in chronic inflammation. 相似文献
13.
T Suda R Murray C Guidos A Zlotnik 《Journal of immunology (Baltimore, Md. : 1950)》1990,144(8):3039-3045
Many cytokines (including IL-1, IL-2, IL-4, IL-6, and TNF-alpha) have been shown to induce thymocyte proliferation in the presence of PHA. In this report, we demonstrate that certain cytokine combinations induce thymocyte proliferation in the absence of artificial comitogens. IL-1 alpha, IL-6, and TNF-alpha enhanced the proliferation of whole unseparated thymocytes in the presence of IL-2, whereas none of them induced thymocyte proliferation alone. In contrast, of these three enhancing cytokines, only IL-6 enhanced IL-4-induced proliferation. We also separated thymocytes into four groups based on their expression of CD4 and CD8, and investigated their responses to various cytokines. The results indicate that each cytokine combination affects different thymocyte subsets; thus, IL-1 alpha enhanced the proliferation of CD4-CD8- double negative (DN) thymocytes more efficiently than IL-6 in the presence of IL-2, whereas IL-6 enhanced the responses of CD4+CD8- and CD4-CD8+ single positive (SP) thymocytes to IL-2 or IL-4 better than IL-1 alpha. TNF-alpha enhanced the proliferation of both DN and both SP subsets in the presence of IL-2 and/or IL-7. None of these combinations induced the proliferation of CD4+CD8+ double positive thymocytes. Finally, DN were separated into CD3+ and CD3- populations and their responsiveness was investigated, because recent reports strongly suggest that CD3+ DN thymocytes are a mature subset of different lineage rather than precursors of SP thymocytes. CD3+ DN proliferated in response to IL-7, TNF-alpha + IL-2, and IL-1 + IL-2. CD3- DN did not respond to IL-7 or to IL-1 + IL-2, but did respond to TNF-alpha + IL-2. Finally, we detected TNF-alpha production by a cloned line of thymic macrophages, as well as by DN adult thymocytes. These results suggest that cytokines alone are capable of potent growth stimuli for thymocytes, and indicate that different combinations of these molecules act selectively on thymocytes at different developmental stages. 相似文献
14.
Kurowska-Stolarska M Kewin P Murphy G Russo RC Stolarski B Garcia CC Komai-Koma M Pitman N Li Y Niedbala W McKenzie AN Teixeira MM Liew FY Xu D 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(7):4780-4790
Type 2 cytokines (IL-4, IL-5, and IL-13) play a pivotal role in helminthic infection and allergic disorders. CD4(+) T cells which produce type 2 cytokines can be generated via IL-4-dependent and -independent pathways. Although the IL-4-dependent pathway is well documented, factors that drive IL-4-independent Th2 cell differentiation remain obscure. We report here that the new cytokine IL-33, in the presence of Ag, polarizes murine and human naive CD4(+) T cells into a population of T cells which produce mainly IL-5 but not IL-4. This polarization requires IL-1R-related molecule and MyD88 but not IL-4 or STAT6. The IL-33-induced T cell differentiation is also dependent on the phosphorylation of MAPKs and NF-kappaB but not the induction of GATA3 or T-bet. In vivo, ST2(-/-) mice developed attenuated airway inflammation and IL-5 production in a murine model of asthma. Conversely, IL-33 administration induced the IL-5-producing T cells and exacerbated allergen-induced airway inflammation in wild-type as well as IL-4(-/-) mice. Finally, adoptive transfer of IL-33-polarized IL-5(+)IL-4(-)T cells triggered airway inflammation in naive IL-4(-/-) mice. Thus, we demonstrate here that, in the presence of Ag, IL-33 induces IL-5-producing T cells and promotes airway inflammation independent of IL-4. 相似文献
15.
Yoshimura T Takeda A Hamano S Miyazaki Y Kinjyo I Ishibashi T Yoshimura A Yoshida H 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(8):5377-5385
Recent lines of evidence have demonstrated that IL-27, a newly identified IL-12-related cytokine, has two apparently conflicting roles in immune responses: one as an initiator of Th1 responses and the other as an attenuator of inflammatory cytokine production. Although the IL-27-mediated Th1 initiation mechanism has been elucidated, little is known about the molecular basis for the suppression of cytokine production. In the present study, we demonstrated that IL-27 suppressed the production of various proinflammatory cytokines by fully activated CD4+ T cells while it had no effect on the cytokine production by CD4+ T cells at early phases of activation. IL-27 also suppressed IL-17 production by activated CD4+ T cells, thereby counteracting IL-23, another IL-12-related cytokine with proinflammatory effects. In fully activated CD4+ T cells, STAT3 was preferentially activated by IL-27 stimulation, whereas both STAT1 and 3 were activated by IL-27 in early activated CD4+ T cells. Lack of STAT3 in fully activated cells impaired the suppressive effects of IL-27. These data indicated that the preferential activation of STAT3 in fully activated CD4+ T cells plays an important role in the cytokine suppression by IL-27/WSX-1. 相似文献
16.
IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis 总被引:7,自引:0,他引:7
Klimiuk PA Goronzy JJ Weyand CM 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(7):4293-4299
T lymphocytes are a major component of the inflammatory infiltrate in rheumatoid synovitis, but their exact role in the disease process is not understood. Functional activities of synovial T cells were examined by adoptive transfer experiments in human synovium-SCID mouse chimeras. Adoptive transfer of tissue-derived autologous CD8+ T cells induced a marked reduction in the activity of lesional T cells and macrophages. Injection of CD8+, but not CD4+, T cells decreased the production of tissue IFN-gamma, IL-1beta, and TNF-alpha by >90%. The down-regulatory effect of adoptively transferred CD8+ T cells was not associated with depletion of synovial CD3+ T cells or synovial CD68+ macrophages, and it could be blocked by Abs against IL-16, a CD8+ T cell-derived cytokine. In the synovial tissue, CD8+ T cells were the major source of IL-16, a natural ligand of the CD4 molecule that can anergize CD4-expressing cells. The anti-inflammatory activity of IL-16 in rheumatoid synovitis was confirmed by treating synovium-SCID mouse chimeras with IL-16. Therapy for 14 days with recombinant human IL-16 significantly inhibited the production of IFN-gamma, IL-1beta, and TNF-alpha in the synovium. We propose that tissue-infiltrating CD8+ T cells in rheumatoid synovitis have anti-inflammatory activity that is at least partially mediated by the release of IL-16. Spontaneous production of IL-16 in synovial lesions impairs the functional activity of CD4+ T cells but is insufficient to completely abrogate their stimulation. Supplemental therapy with IL-16 may be a novel and effective treatment for rheumatoid arthritis. 相似文献
17.
Mice 6 days after thermal injury (TI-mice) did not respond to lipopolysaccharide (LPS) stimulation for production of serum interleukin 12 (IL-12; 2 h after LPS stimulation, <20 pg/ml in TI-mice; 1091+/-162 pg/ml in normal mice). However, 2 h after LPS stimulation, 1456+/-118 pg/ml of IL-12 were demonstrated in sera of TI-mice previously treated with a 10 mg/kg i.p. dose of glycyrrhizin (GR). IL-12 was not induced by LPS in sera of normal mice inoculated with burn-associated type 2 T cells (IL-4/IL-10-producing CD8+CD11b+TCRgamma/delta+T cells isolated from spleens of TI-mice). However, IL-12 production was induced by LPS in sera of these mice previously treated with GR or a mixture of monoclonal antibodies (mAbs) for type 2 cytokines. Also, IL-12 production was induced by LPS in TI-mice inoculated with CD4+T cells from spleens of GR-treated normal mice (GR-CD4+T cells, 5x10(6)cells/mouse). Since GR-CD4+T cells have been shown to be antagonistic cells against production of type 2 cytokines by burn-associated type 2 T cells, these results indicate that IL-12 unresponsiveness shown in TI-mice is recovered by GR through the regulation of burn-associated type 2 T cell responses. 相似文献
18.
Ansari NA Kumar R Gautam S Nylén S Singh OP Sundar S Sacks D 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(7):3977-3985
IL-10 is believed to underlie many of the immunologic defects in human visceral leishmaniasis (VL). We have identified CD4(+)CD25(-)Foxp3(-) T cells as the major source of IL-10 in the VL spleen. IL-27, a member of the IL-6/IL-12 cytokine family, has been shown to promote development of IL-10-producing T cells, in part by upregulating their production of autocrine IL-21. We investigated whether IL-27 and IL-21 are associated with human VL. IL-27 was elevated in VL plasma, and at pretreatment, spleen cells showed significantly elevated mRNA levels of both IL-27 subunits, IL-27p28 and EBI-3, as well as IL-21, compared with posttreatment biopsies. CD14(+) spleen cells were the main source of IL-27 mRNA, whereas CD3(+) T cells were the main source of IL-21. IL-27 mRNA could be strongly upregulated in normal donor macrophages with IFN-γ and IL-1β, conditions consistent with those in the VL spleen. Last, a whole-blood assay revealed that most VL patients could produce Ag-specific IFN-γ and IL-10 and that the IL-10 could be augmented with recombinant human IL-21. Thus, proinflammatory cytokines acting on macrophages in the VL spleen have the potential to upregulate IL-27, which in turn can induce IL-21 to expand IL-10-producing T cells as a mechanism of feedback control. 相似文献
19.
W R Herzog N R Ferreri W Ptak P W Askenase 《Journal of immunology (Baltimore, Md. : 1950)》1989,143(10):3125-3133
The elicitation of delayed-type hypersensitivity (DTH) requires an early-acting Thy-1+ cell that produces an Ag-specific, non-MHC-restricted factor that initiates DTH by sensitizing the local tissue for release of the vasoactive amine serotonin. We characterized the phenotype of this DTH-initiating cell by treating cells from sensitized mice with different antibodies and then either with rabbit C or anti-Ig panning or bead separation to deplete various subpopulations. We then transferred these cells i.v. into naive recipients that were challenged to elicit DTH. Our findings indicate that the early DTH-initiating cell is Thy-1+, Lyt-1+, CD4-, CD8- and CD3-, whereas the classical, late DTH effector T cell is Thy-1+, Lyt-1+, CD4+, CD8-, and CD3+. We hypothesize that DTH-initiating cells are primitive T cells with Ag receptors that can bind Ag without MHC-restriction. This hypothesis was supported by the finding that two different antibodies, that both bind T cell-derived Ag-binding molecules, eliminated the DTH-initiating, cell but did not affect the late component, MHC-restricted CD4+, CD3+ T cell. Additional experiments with antibodies against restricted determinants of the T-200 glycoprotein family (CD45R) showed that the early but not the late cell is positive for B220, which is usually present on B cells, and on some activated T cells. Also, the DTH-initiating cell is Il-2R-, but Il-3R+; whereas the late component DTH T cell is IL-2R+ and IL-3-. Our findings suggest that DTH-initiating cells may be Ag-specific lymphoid precursor cells that arise before final differentiation along the pathway leading to mature T or B cells. Our results indicate that antigen-specific Thy-1+, CD3-, CD4-, CD8- cells function in vivo to initiate DTH reactions. 相似文献
20.
IL-6 and IL-1 synergize to stimulate IL-2 production and proliferation of peripheral T cells 总被引:9,自引:0,他引:9
Purified T cells can be induced to proliferate and to produce the autocrine growth factor IL-2 with mAb to the TCR and costimulatory cytokines. In a previous report we demonstrated that human IL-6 stimulates IL-2 production and proliferation of purified T cells, in conjunction with the insolubilized anti-TCR V beta 8 mAb, F23.1. Here we show that when CD4+ T cells are rigorously purified to greater than 99% CD4+CD8-, they respond only weakly to F23.1 and IL-6. Instead, there is an additional requirement for IL-1, which dramatically synergizes with IL-6 to induce prolonged (greater than 7 days) proliferative responses and IL-2 production. Similar results were observed when the highly mitogenic anti-CD3 mAb 145-2C11 was substituted for F23.1. The proliferation induced by F23.1, IL-1, and IL-6 was substantially (greater than 80%) inhibited by a mAb to mouse IL-2, and was not inhibited by an anti-IL-4-mAb. In accordance with this finding, medium conditioned by the activated CD4+ cells contained large amounts of IL-2, which increased over a 7-day culture period. These results demonstrate that IL-6 and IL-1 stimulate T cell proliferation by inducing production of the autocrine growth factor IL-2. In addition, the two lymphokines must be present simultaneously for activation to occur. The possible roles of IL-6 and IL-1 in IL-2 gene regulation and in Ag-induced T cell activation are discussed. 相似文献