Ovalbumin-specific induction of IL2 responsiveness in lymphocytes from patients with hen egg allergy and its regulation by the culture supernatant of normal lymphocytes.

Interleukin 2 (IL2) responsiveness of ovalbumin (OVA)-stimulated lymphocytes from patients with hen-egg allergy was studied. The number of viable cells of 5-day cultured lymphocytes stimulated with OVA was increased by an additional three days incubation with recombinant IL2. This phenomenon was not observed when the lymphocytes of patients allergic to OVA but not to Dermatophagoides farinae extract antigen (Df) were stimulated with Df. Normal lymphocytes stimulated with OVA expressed Tac antigen (low affinity IL2 receptor) but, in contrast to those from the allergic patients, did not absorb nor respond to IL2. The induction of OVA-specific IL2 responsiveness in patient lymphocytes was markedly suppressed on the addition of culture supernatant from OVA-stimulated normal T cells, but Df-specific IL2 responsiveness of the lymphocytes from Df-sensitized patients with bronchial asthma was not suppressed by the same supernatant. The supernatant of lymphocytes from allergic patients did not show such suppressive effect. The patient lymphocytes whose IL2 responsiveness was suppressed with the supernatant from normal lymphocytes still expressed Tac antigen. These observations suggest that the culture supernatant of normal T lymphocytes stimulated with OVA contained an antigen-specific factor suppressing the induction of IL2 responsiveness of OVA-stimulated patient lymphocytes. The production of such a suppressive factor was impaired in the patient, and further, the factor may have inhibited the triggering signal of IL2 receptors having absorbed IL2. The existence of some allogeneic barrier between the factor(s) and patient lymphocytes was suggested, since the supernatant from OVA-stimulated normal T cells did not necessarily suppress the response of all patients tested.     

Allergen-specific induction of interleukin-2 (IL-2) responsiveness in lymphocytes from children with asthma. I. Antigen specificity and initial events of the induction

Interleukin-2 (IL-2) responsiveness of Dermatophagoides farinae (Df)-stimulated lymphocytes from children with bronchial asthma was studied. Six-day culture of lymphocytes from allergic patients increased after an additional 3 days of incubation with recombinant IL-2. This phenomenon was not observed when the lymphocytes of patients allergic to Df were stimulated with ovalbumin (OVA). Normal lymphocytes stimulated with Df expressed Tac antigen (low-affinity IL-2 receptor) but, in contrast to the patients' lymphocytes, did not absorb nor respond to IL-2. Nonadherent responder cells cultured with Df-pulsed autologous adherent cells acquired IL-2 responsiveness, but those cultured with OVA-pulsed adherent cells did not. The monoclonal antibody to HLA-DQ framework (Leu 10 and clonab DQ), but not to HLA-DR framework (OKIa1) and HLA-DP (HLA-DP and clonab DP-DR), blocked the antigen-presenting cells from inducing IL-2 responsiveness. Nonadherent responder cells depleted of OKT4 (CD4)-positive cells failed to acquire IL-2 responsiveness, whereas depletion of OKT8 (CD8) cells had no impact. Taken as a whole, the results indicate that DQ-bearing adherent cells from allergic donors play a key role in presenting Df antigen to allergen-specific responder T cells, which are very likely to be members of the OKT4 positive subset.     

Modulation of human T cell functions by surface sulphydryl groups: differential effects on IL-2 production and responsiveness.

An impermeable thiol blocker has been used to investigate the role of sulphydryl (SH) groups in the production of and responsiveness to IL-2 by normal human T lymphocytes. Surface SH blockade of mononuclear cells prior to incubation with mitogen (phytohaemagglutinin, concanavalin A, CD3 MoAb) had no effect on production of IL-2 but markedly impaired cellular responsiveness to exogenous IL-2. Studies using MoAbs indicated that this effect was accompanied by decreased expression of both the CD25 and p75 subunits of the IL-2 receptor. Blocking surface SH groups did not affect binding of IL-2 to p75 on unstimulated mononuclear cells, but inhibited binding to high-affinity receptors on a T lymphoma cell line. The data are consistent with the hypothesis that sulphydryl groups on the IL-2 receptor are required for its function and may be involved in the interaction of the CD25 and p75 subunits leading to generation of the high-affinity binding site. The surface thiol identified on the IL-2 receptor may be a candidate for oxidation on cells from patients with chronic inflammatory diseases such as rheumatoid arthritis and thus contribute to the aberrant function of T cells in these patients.     

Suppressive effect of azelastine on the induction of Df antigen specific IL-2 responsiveness in lymphocytes from patients with bronchial asthma

Effect of azelastine on the induction of Dermatophagoides farinae (Df)-antigen specific IL-2 responsiveness of the lymphocytes was examined. Azelastine suppressed the induction of IL-2 responsiveness induced by Df antigen in peripheral blood mononuclear cells from patients with bronchial asthma in a dose dependent manner. Azelastine suppressed antigen presenting adherent cells but not non-adherent responder cells (T cell rich fraction). The antigen specific IL-2 responsiveness induced by purified protein derivative (PPD) in healthy adults was also suppressed by this drug, but not by concanavalin A (Con A). These data suggest that Azelastine suppresses the antigen specific lymphocyte reactions, and that these effects are based on the weak suppressive effect on antigen presenting and/or processing pathway.     

IL-4 down-regulates the responsiveness of human intraepithelial lymphocytes

IL-4 is an important regulator of intestinal inflammation, yet little is known regarding its action on intestinal lymphocytes. Intestinal lymphocytes were isolated from jejunal mucosa of patients undergoing gastric bypass operations for morbid obesity. The impact of IL-4 was measured by its effects on proliferation using ³H-thymidine incorporation, IL-2 production using the CTLL assay, and IL-2 receptor generation using immunofluorescence. The production of IL-4 was measured by ELISA. IL-4 significantly inhibited the proliferation of intraepithelial lymphocytes (IEL) to a variety of stimuli as well as the development of lymphokine-activated killer (LAK) cells. In contrast, it had no effect on the proliferation of CD8⁺ T cells from peripheral blood. The inhibitory effect of IL-4 on IEL did not occur during activation, since IL-2 production and receptor expression were not altered. Rather, it occurred during cell cycling, since over 50% inhibition resulted whether IL-4 was added at the initiation of an IL-2-stimulated culture or after 24 or 48 h incubation. IL-4 was secreted by activated lamina propria lymphocytes (LPL) but not by IEL. IL-4,produced by activated LPL, may enter the epithelial compartment and down-regulate responsiveness of IEL.     

Human IFN-gamma up-regulates IL-2 receptors in mitogen-activated T lymphocytes.

This study examined the role of human recombinant interferon-gamma (rIFN-gamma) in the expression of interleukin-2 receptors (IL-2R) by human T lymphocytes. rIFN-gamma enhanced total numbers of IL-2R in mitogen-activated but not resting T cells. Scatchard plot analysis indicated that rIFN-gamma increased both high- and low-affinity receptors, with a predominant effect on the latter. Phytohaemagglutinin (PHA)-activated T cells treated with IFN-gamma showed higher IL-2 binding and greater IL-2 internalization and degradation than cells treated with PHA alone. There was a corresponding increase of mitogen-driven proliferative responses, indicating an increase of functional receptors in IFN-treated cultures. IFN-gamma may influence T-cell activation and proliferation by enhancing expression of IL-2R and promoting IL-2 uptake by mitogen-activated lymphocytes.     

Suppressive effect of Saibokuto on Dermatophagoides farinae (Df) antigen-induced IL2 responsiveness of lymphocytes from asthmatic children

The effect of Saibokuto on induction of antigen specific IL2 responsiveness was studied. Saibokuto suppressed the induction of IL2 responsiveness induced by Dermatophagoides farinae (Df) antigen in peripheral blood mononuclear cells from patients with bronchial asthma. Saibokuto-pretreated adherent cells failed to present Df antigen to non-adherent responding T cells for induction of their IL2 responsiveness. The same dose of Saibokuto had no impact on non-adherent cells. Saibokuto also suppressed the induced IL2 responsiveness of lymphocytes from the same patients on stimulation wit PPD, but not with Con A. These combined data suggests that Saibokuto has a weak immunosuppressive effect on Df induced IL2 responsiveness of lymphocytes from asthmatic children. Effect of Saibokuto on induction of antigen specific IL2 responsiveness was studied. Saibokuto suppressed the induction of IL2 responsiveness induced by Dermatophagoides farinae (Df) antigen in peripheral blood mononuclear cells from patients with bronchial asthma. Saibokuto-pretreated adherent cells failed to present Df antigen to non-adherent responding T cell for induction of their IL2 responsiveness. Non-adherent cells had no impact by the same dose of Saibokuto. Saibokuto also suppressed the induced IL2 responsiveness of lymphocytes from the same patient on stimulation with PPD, but not Con A. These combined data suggest that Saibokuto has a weak immunosuppressive effect on Df induced IL2 responsiveness of lymphocytes from asthmatic children. Effect of Saibokuto on induction of antigen specific IL2 responsiveness was studied. Saibokuto suppressed the induction of IL2 responsiveness induced by Dermatophagoides farinae (Df) antigen in peripheral blood mononuclear cells from patients with bronchial asthma. Saibokuto-pretreated adherent cells failed to present Df antigen to non-adherent responding T cell for induction of their IL2 responsiveness. Non-adherent cells had no impact by the same dose of Saibokuto. Saibokuto also suppressed the induced IL2 responsiveness of lymphocytes from the same patient on stimulation with PPD, but not Con A. These combined data suggest that Saibokuto has a weak immunosuppressive effect on Df induced IL2 responsiveness of lymphocytes from asthmatic children.     

CD4+ CD45RA+ T cells modulate allergen-induced interleukin 2 responsiveness in human lymphocytes.

Peripheral blood lymphocytes from nonallergic individuals acquired responsiveness to interleukin 2 (IL2) after stimulation with ovalbumin (OVA) or Dermatophagoides farinae (Df) antigens when they were pretreated with the CD45RA antibody, which has been shown to define the suppressor inducer subset of CD4+ cells and also to block its suppressor activity. The effect provided by the CD45RA antibody was lost if the lymphocytes had initially been activated with the OVA of Df antigens. The magnitude of the responses was comparable to the allergen-induced responses observed in OVA- or Df-sensitized lymphocytes from allergic patients. The pre-existing IL2 responsiveness in the patients was not increased by the CD45RA antibody pretreatment. However, the CD45RA antibody pretreatment gave rise to Df-induced IL2 responsiveness in the lymphocytes of the patients sensitized with OVA but not with Df; conversely, OVA-induced IL2 responsiveness was enhanced in Df- but not in OVA-sensitized lymphocytes. The CD45RA antibody apparently acts on CD4+ T cells, but not on CD8+ T cells, to induce the IL2 response. A further dissection of normal CD4+ T cells indicated that CD4+45RA- T cells preferentially respond to IL2 after stimulation with OVA or Df antigens. Since normal CD4+45RA+ T cells did not show antigen-induced IL2 responsiveness even after pretreatment with the CD45RA antibody, it is unlikely that the CD45RA antibody stimulates CD4+45RA+ T cells to become responsive to IL2 after antigenic challenge. Alternatively, CD4+45RA+ T cells may modulate the activity of CD4+45RA- T cells, which are potentially responsive to IL2 by antigenic stimulation and thus provide tolerance in nonallergic lymphocytes. Collectively, a defective suppressor activity of CD4+45RA+ T cells may exist in patients with hen-egg allergy and/or bronchial asthma, which may cause lymphocytes to be hyperreactive to OVA or Df antigens.     

Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes

Multiple myeloma (MM) is a cancer of plasma cells, characterized by profound suppression of host immune responses. Here we show that MM cell lines significantly suppress the proliferation, blasting, response to interleukin-2 (IL-2), and expression of CD25 by concanavalin A (Con A)-activated or allostimulated peripheral blood T lymphocytes. T cells arrest in the G1 stage of the cell cycle, and do not enter the IL-2 autocrine growth pathway. T cell inhibition was mediated by a soluble factor. MM cell lines did not produce IL-10 but did produce large amounts of transforming growth factor beta1 (TGF-beta1). T cells were assessed for their ability to respond to IL-2 when co-cultured with MM cells in the presence or absence of the TGF-beta inhibitor, TGF-beta latency-associated peptide (LAP). MM cells suppressed IL-2 responses but this inhibition was completely reversed by TGF-beta LAP. A CD25-, IL-2-dependent blast cell line was not inhibited by MM cells or rhTGF-beta, confirming the specificity of the inhibition mechanism for the IL-2 autocrine growth pathway. We conclude that MM cells suppress T cells in their entry into the autocrine IL-2/CD25 pathway and in response to IL-2, and that TGF-beta has a significant role to play.     

Study on the effect of disodium cromoglycate (DSCG) on antigen induced IL-2 responsiveness

We tested the effects of disodium cromoglycate (DSCG) on antigen-induced IL-2 responsiveness in lymphocytes from patients with atopic dermatitis and/or bronchial asthma. Patient lymphocytes pretreated with 5 x 10(3) micrograms/ml DSCG for 24 or 48 hours failed to induce the responsiveness to IL-2 on stimulation with Dermatophagoides farinae (Df) or ovalbumin (OVA) antigen. DSCG-treated adherent cells were blocked to present the antigen to nonadherent responding cells for induction of IL-2 responsiveness. In contrast, DSCG-treated non-adherent cells, recombined with antigen-activated adherent cells, acquired IL-2 responsiveness. However, Con A-activated lymphocytes from the same patients were not affected by the same treatment. The results indicate that DSCG is capable of suppressing antigen-induced IL-2 responsiveness but not the response induced by mitogen such as Con A.     

Effect of ketotifen on antigen-induced interleukin 2 (IL-2) responsiveness in lymphocytes from patients with atopic dermatitis and/or bronchial asthma

We tested the effect of Ketotifen (4-(1-methyl-4-piperidylidene)-4H- benzo[4,5] cyclohepta[1,2-b]thiophen-10(9H)-one hydrogen (fumarate) on the induction of allergen-induced IL-2 responsiveness in lymphocytes from patients with atopic dermatitis and/or bronchial asthma. Ovalbumin (OVA)- and/or Dermatophagoides farinae(Df)-induced IL-2 responsiveness was increased in almost all patients (1-15 years old) before Ketotifen treatment. Two to 12 months administration of Ketotifen (0.06 mg/kg/day) decreased activity of the response in 7 out of 9 cases corresponding to improvement of clinical symptoms. In in-vitro studies, antigen presenting cells (adherent cells) from the patient pretreated with 5, 50 and 500 ng/ml doses of Ketotifen for 12 h failed to present OVA or Df antigen to T-cells for induction of IL-2 responsiveness. Antigen-pulsed adherent cells also failed to induce the response of the T-cells pretreated with 50 and 500 ng/ml doses of Ketotifen but not with a 5 ng/ml dose. A 50 ng/ml dose of Ketotifen did not affect T-cells for induction of the response. In contrast, the treated adherent cells are capable of presenting PPD antigen or Con A for the induced response. The combined data indicate that induction of IL-2 responsiveness of peripheral blood lymphocytes on stimulation with nominal antigen may reflect an immune response to allergen in patients with allergy and a weak immunosuppressive effect of Ketotifen seems to block the response in the pathogenic process of allergic diseases.     

Acute activation of CD8+ T lymphocytes in interleukin-2-treated HIV-infected patients. ANRS-048 IL-2 Study Group. Agence Nationale de Recherches sur le SIDA.

CD8+ T lymphocytes play a key role in the control of HIV infection, through both cytotoxic and noncytotoxic mechanisms. To study in vivo effects of interleukin-2 (IL-2) treatment on this cell compartment, the level of activation of CD8+ T lymphocytes was evaluated before and just after 5-day administration of IL-2 in 16 HIV-infected patients. The serum level of soluble CD25 and of soluble CD8 significantly increased following IL-2 administration. The number of mRNA molecules coding for perforin and granzyme B, two enzymes that are contained in granules of cytotoxic cells, also significantly increased in peripheral blood mononuclear cells and in purified CD8+ cells (p < .001). Variations of plasma HIV viremia and perforin gene expression following IL-2 administration were inversely correlated (p = .023), suggesting that IL-2-induced activation of CD8+ T lymphocytes contributes to limit HIV replication in vivo. In contrast to perforin and granzyme B gene expression, IL-2 administration did not increase the expression of macrophage inhibitory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated-on-activation normal T-expressed and secreted (RANTES) genes. These findings indicate that CD8+ T lymphocytes in HIV-infected patients are acutely activated by IL-2 treatment, which may improve long-term control of HIV infection.     

Activation and proliferation of normal resting human T lymphocytes in serum-free culture: role of IL-4 and IL-6

Purified human T lymphocytes, completely depleted of accessory cells [i.e. monocytes, large granular lymphocytes (LGL) and B lymphocytes], have been grown in serum-free culture in presence of a mitogenic lectin (phytohaemagglutinin, PHA) and different recombinant cytokines. Only IL-2 and IL-4 induced a marked stimulation of [3H] thymidine ([3H]TdR) uptake, cell proliferation and expression of activation markers [transferrin receptor (TrfR), IL-2R]. The other cytokines (IL-1 alpha, IL-1 beta, IFN-gamma, GM-CSF, TNF-alpha) had no significant effect, except for a moderate, but significant, stimulation of [3H]TdR uptake induced by IL-3. Simultaneous addition of IL-4 and anti-IL-2 neutralizing monoclonal antibodies (mAb) did not modify the effects induced by IL-4 alone. Furthermore, IL-2 was not detected in the supernatant of T cells grown in the presence of PHA and IL-4. Thus, our results indicate that IL-4 acts on T lymphocytes independently of IL-2. We also observed that IL-6 moderately activates DNA synthesis in PHA-stimulated T lymphocytes, but markedly potentiates the proliferative effect of suboptimal amounts of IL-2. In conclusion, the present study suggests that B-cell growth factors, in addition to IL-2, control the proliferation of normal circulating T lymphocytes.     

The distribution of interleukin-2 receptor bearing lymphocytes in multiple sclerosis: evidence for a key role of activated lymphocytes.

The identification of T cells in the brain using monoclonal antibodies has suggested a role for T cells in the pathogenesis of multiple sclerosis (MS). In the present study the monoclonal antibody anti-Tac, shown to react with interleukin-2 (IL-2) receptors expressed on activated T cells, was used to determine levels of recently activated T cells in blood, cerebrospinal fluid (CSF) and brain sections from MS patients at different stages of disease. The CSF of MS patients contained much higher numbers of IL-2 receptor positive lymphocytes (up to 67%) than blood cells from the same patients, or the CSF of patients with non-inflammatory neurological diseases. In histological sections of the brain of MS patients with active disease, perivascular lymphocytes expressing IL-2 receptors were detected, as were lymphocytes containing IL-2. In contrast, these were absent in brain sections from patients with chronic MS, secondary demyelination or from normal controls. These observations in CSF and brain suggest that in multiple sclerosis, T-cell activation is occurring within the CNS and not in peripheral lymphoid tissue.     

Expression of p55 (Tac) interleukin-2 receptor (IL-2R), but not p75 IL-2R, in cultured H-RS cells and H-RS cells in tissues.

The authors studied the secretion of interleukin-2 (IL-2), the expression of interleukin-2 receptors (IL-2R; p55/Tac and p75), and the response to exogenous IL-2 by cultured Hodgkin's Reed-Sternberg cells (cell lines HDLM-1, HDLM-1d, and KM-H2) and T cells (H9, HuT78, HuT102, MOLT-4, and MT-2). All of these cells did not produce IL-2 or produced it in undetectable amounts, and their growth was not affected by the addition of anti-IL-2 or anti-IL-2R antibodies. This indicates that H-RS cells in long-term culture, as well as T cells, can grow independently of IL-2. The three H-RS cell lines, as well as two of the T-cell lines (HuT102 and MT-2), expressed Tac, whereas the other three T-cell lines were Tac negative. Expression of p75 was noted in the two Tac-positive T-cell lines, but not in cultured H-RS cells. The expression of Tac and p75 in HuT102 and MT-2 cells correlated well with their capacity to proliferate on treatment with exogenous IL-2. On IL-2 treatment, nucleic-acid uptake in Tac/p75-positive T cells increased approximately four- to sixfold, whereas the Tac/p75-negative T cells did not show increased proliferation. Unlike the T cells, the Tac-positive H-RS cells did not respond to IL-2. The lack of a proliferative response to IL-2 appears to be related to the absence of p75 in H-RS cells. A similar pattern (Tac positivity and p75 negativity) was noted in H-RS cells in lymph nodes involved by Hodgkin's disease. Thus the exogenous IL-2 released by surrounding T lymphocytes may not cause the proliferative activity of H-RS cells because of the lack of high-affinity IL-2 receptors in the latter cells. In contrast to H-RS cells in culture, H-RS cells in tissues were stained by a specific anti-IL-2 monoclonal antibody. This indicates that the expression of IL-2 or an IL-2-like substance by H-RS cells in tissues may be responsible, in part, for the great increase in the number of reactive T lymphocytes in tissues involved by Hodgkin's disease.     

Stimulating and differentiation factors for human B lymphocytes in systemic lupus erythematosus.

T cells from 18 untreated SLE patients produced significantly more B cell growth factor (BCGF) than did those from normal subjects. Those from SLE patients with active disease produced significantly more than did those from patients with inactive disease. The response to BCGF of SAC-stimulated B lymphocytes from SLE patients was higher than that of B lymphocytes from normal individuals. Similarly preactivated B cells from five of seven SLE patients also proliferated upon the addition of interleukin 1 (IL-1) whereas those of normal subjects did not. Simultaneous addition of IL-1 and BCGF had a synergistic proliferative effect on B cells from two of seven SLE patients but not on any of the controls. Interleukin 2 (IL-2) had no proliferative effect in either SLE or normal B cells. Supernatant fractions from T cells of seven of 10 patients with active SLE and three of 10 with inactive SLE induced more IgG production by CESS cells than did those of normal subjects indicating a higher production of B cell differentiation factor by SLE T cells than by those of controls. Our findings may explain the reported preactivation and predifferentiation of peripheral blood B cells from SLE patients and give insight into the mechanisms leading to the production of autoantibodies in this disease.     

HL—60细胞产生的肿瘤免疫抑制因子对T细胞的作用及其生物学特性

白血病细胞培养上清液和白血病人血清能抑制PHA—P诱导的人外周血T淋巴细胞的增殖;抑制白细胞介素2(IL—2)的产生和反应性。以正常2BS人胚肺细胞培养上清液和正常人血清作对照则无抑制作用。白血病细胞培养上清液无细胞毒作用。聚丙烯酰胺凝胶电泳(PAGE)结果表明,来源HL—60人早幼粒白血病细胞的肿瘤免疫抑制因子(tumor-derived immunosuppressive factor,TDSF)的分子量约为87KD,其化学本质为蛋白质。抗急非淋白血病药物对这种TDSF的分泌有部分抑制作用。     

Analysis of CD3 antigen expression in patients with ataxia-telangiectasia.

The expression of CD3 molecules by the lymphocytes of five patients with ataxia-telangiectasia was examined using the murine monoclonal antibody OKT3. By immunofluorescent staining, fewer of the patients' peripheral blood mononuclear cells and purified T cells expressed CD3 compared with normals. The proliferative response of the patients' cells to OKT3 was also less than normal. However, the mononuclear cells from all five patients produced IL-2 after OKT3 stimulation; in four patients IL-2 was normal, while one patient produced greater than normal levels. While the expression of cellular IL-2 receptors and the release of these receptors into culture supernatants was generally less in ataxia-telangiectasia patients, the levels of receptor expression were not significantly less than normal. As analysed by sodium dodecyl sulphate polyacrylamide gel electrophoresis, the CD3 molecules from ataxia-telangiectasia patients' lymphocytes were no different from those of normal individuals. These results suggest that patients with ataxia-telangiectasia have structurally normal CD3 molecules which may be used to activate cells normally for some but not all T cell functions.     

白血病细胞相关的免疫抑制活性对正常人IL－2及CD抗原的作用

６５例白血病患者的细胞制备物（白细胞培养上清与溶解物）测定对正常人ＰＢＬ的ＩＬ－２产生、ＩＬ－２反应性及ＣＤ４、ＣＤ８、ＣＤ２５抗原表达的影响，并探讨与抑制淋转和ＭＬＲ的关系。结果表明制备物对ＩＬ－２产生及／或ＩＬ－２反应性的抑制是抑制淋转与ＭＬＲ的主要因素。抑制ＩＬ－２产生及／或ＩＬ－２反应者对正常人ＰＤＬ的ＣＤ４表达有明显抑制，但对ＣＤ８、ＣＤ２５表达未见影响，提示来自白血病细胞的免疫抑制是通过抑制淋巴细胞ＣＤ４表达、ＩＬ－２产生及／或ＩＬ－２反应起作用的。