Expression of inhibitory-motif killer immunoglobulin-like receptor, KIR2DL1, is increased in natural killer cells from women with pelvic endometriosis

Problem:  We investigated inhibitory and activation motif expression of killer immunoglobulin-like receptor (KIR) by natural killer (NK) cells, which may be pathogenetically involved in endometriosis.
Method of study:  We compared cells from 24 Japanese women laparoscopically diagnosed with endometriosis, to cells from 25 women with other laparoscopic diagnoses. KIR expression by NK cells was assessed in peripheral blood (PB) and peritoneal fluid (PF) by flow cytometry. Intracellular immunoreceptor tyrosine-based (IT) inhibitory and activation motifs (ITIM and ITAM) of KIR in PB was assessed by Western blotting.
Results:  ITIM-KIR expression by PB NK cells was significantly and similarly greater than ITAM-KIR expression in women with and without endometriosis. Percentages of CD56⁺ NK cells in PB and PF did not differ significantly between women with and without endometriosis; however, the percentage of CD158a⁺ cells among CD56⁺ NK cells in PB and PF was significantly higher in women with than without endometriosis.
Conclusions:  ITIM-KIR expressing NK cells might confer tolerance to peritoneal endometriotic implants.     

The Suppression of Peritoneal Cellular Immunity in Women With Endometriosis Could Be Restored After Gonadotropin Releasing Hormone Agonist Treatment

PROBLEM: Our previous study reported that peritoneal natural killer (NK) cytotoxicity and CD3⁺CD25⁺ lymphocyte subpopulation were suppressed in women with advanced endometriosis. Whether these phenomena are general for all stages of endometriosis and whether these alterations could be restored by long-term use of gonadotropin releasing hormone agonist (GnRHa) are further tested in this study. METHOD: Lymphocyte subpopulations (B cells, NK cells, T cells, and T-cell activation markers such as CD69, HLA-DR, and CD25) and NK cell cytotoxicity of peripheral blood and peritoneal fluid by dual-color flow cytometry and ^5lCr release assay in 30 cases of endometriosis were compared with those in 26 controls. We also compared these changes before and after 6-month treatment with GnRHa for advanced endometriosis. RESULTS: Compared with the controls, only those women with advanced endometriosis showed lower NK cytotoxicity in peritoneal fluid mononuclear cells (PFMC). The CD3⁺CD69⁺ lymphocyte subpopulation decreased in peripheral blood mononuclear cells (PBMC) of advanced endometriosis, while the CD3⁺CD25⁺ lymphocyte subpopulation decreased in both PBMC and PFMC of mild and advanced endometriosis. After GnRHa treatment, the CD3⁺CD69⁺ lymphocyte subpopulation increased in both PBMC and PFMC and the CD3⁺CD25⁺ lymphocyte subpopulation increased in PFMC, but not in PBMC. CONCLUSION: Impaired local immunological function in the PF of endometriosis was confirmed by this study and the impairments could be restored after long-term GnRHa therapy.     

Immature B cells in bone marrow express Fas/FasL

Negative selection is a process by which autoreactive lymphocytes are eliminated from the developing antigen receptor repertoire. The mechanisms regulating negative selection of immature B lymphocytes in the bone marrow are poorly elucidated. Human bone marrow cells were examined in order to investigate the presence of the members of the Fas (APO-1/CD95) system. Here we demonstrate the expression of Fas in immature B lymphocytes (CD10/CD19+/CD40+/sIg+), and the presence of Fas natural ligand (FasL) in CD19+ bone marrow cells. The observed expression of apoptosis-related molecules might indicate how negative selection of autoreactive B cells can occur in human bone marrow.     

CD95 (Fas) ligand expression of Epstein-Barr virus (EBV)-infected lymphocytes: a possible mechanism of immune evasion in chronic active EBV infection

The Epstein-Barr virus (EBV) induces infectious mononucleosis (IM) and can be associated with chronic active EBV infection (CAEBV). Cytotoxic T lymphocytes (CTL) play an important role in excluding EBV-infected cells. Two cytotoxic mechanisms of CTL have been demonstrated: one perforin/granzyme-based and the other Fas (CD95)/Fas ligand (FasL)-based. To clarify these two pathways in CAEBV, we analyzed six patients with CAEBV and four patients with IM using immunohistochemical staining of the lymph nodes. In both CAEBV and IM, CD8⁺ T-cells increased in number, but CD56⁺ natural killer cells were rare. In four of six cases with CAEBV, approximately half the lymphocytes were positive for T cell-restricted intracellular antigens (TIA-1), which were recognized by the cytolytic granules of CTL. In IM, the number of TIA-1 positive cells was smaller than that in CAEBV. Fas-positive lymphocytes were frequently encountered in both CAEBV and IM. However, FasL-positive lymphocytes increased in three of six patients with CAEBV, but not in patients with IM. Except for one case with CAEBV, the number of perforin- and/or granzyme-positive cells was small in number in both CAEBV and IM cases. In double-staining FasL and EBV in situ hybridization, FasL-positive EBV-infected lymphocytes were detected in CAEBV but not in IM. In CAEBV, the Fas/FasL pathway and not perforin pathways appears to play an important role in the pathogenesis. The data suggest that EBV-infected lymphocytes may evade immune attack through the expression of FasL.     

Killer immunoglobulin-like receptor and human leukocyte antigen expression as immunodiagnostic parameters for pelvic endometriosis

PROBLEM: We investigated host immunologic responses to endometriosis by comparing immune cell surface antigens in peripheral blood (PB) and peritoneal fluid (PF) from women with endometriosis with those in PB and PF from other patients. METHOD OF STUDY: Japanese women with endometriosis (n = 56) were compared with controls with other laparoscopic diagnoses (n = 68). PB and PF were collected at the time of laparoscopy for flow cytometry. RESULTS: No significant difference in phenotypic parameters of T cells (CD3, CD4, and CD8), B cells (CD19), natural killer (NK) cells (CD56), or monocytes/macrophages (CD14) was seen between women with and without endometriosis. However, increased killer immunoglobulin-like receptor (CD158a) expression by NK cells and decreased human leukocyte antigen (HLA)-ABC and -DR expression by macrophages, all suggesting decreased functional activation were found in endometriosis. These markers showed significant association with endometriosis by odds ratio, logistic regression, and decision tree analyses. CONCLUSIONS: Increased CD158a(+) NK cells in PB and PF indicated decreased NK cell cytotoxicity in endometriosis, while decreased HLA expression on PF macrophages suggested impaired antigen presentation. Thus, aberrant immune responses by NK cells and macrophages may represent risk factors for endometriosis.     

Immunophenotype of peripheral T lymphocytes, NK cells and expression of CD69 activation marker in patients with recurrent spontaneous abortions, during the mid-luteal phase

PROBLEM: Determination of subpopulations of T lymphocytes, natural killer (NK) and activation status, in peripheral blood during the mid-luteal phase from patients with unexplained recurrent spontaneous abortion (RSA). METHOD OF STUDY: Peripheral blood samples from non-pregnant women with RSA and normal multiparous were taken and evaluated for subpopulations of T lymphocytes: CD4, CD8, ('naive-like' and 'memory-like'), TCR receptor (alphabeta and gammadelta), activation status by CD69(+surface or intracellular)/CD3(+), and NK cells (CD16(+)/CD56(dim)/CD3(-), CD16(+)/CD56 (bright)/CD3(-), CD69(+surface or intracellular)/CD56(+)/CD3(-) cells). RESULTS: The evaluation of T lymphocytes only showed an increase in the expression of CD69 (surface and intracellular) in the RSA group. Additionally, we observed an increase in the total NK cells, CD56(+) NK cells percentages, CD56(dim) NK cells and CD69 NK cells in RSA group. CONCLUSION: These observations support the concept that immunological activation of T lymphocytes and NK cells could be involved in peripheral blood during the mid-luteal phase in patients with unexplained RSA.     

Absence of cytotoxic molecules in CD8- and/or CD56-positive adult T-cell leukaemia/lymphoma

Adult T-cell leukaemia/lymphoma (ATLL) cells usually exhibit a CD4⁺ (helper/inducer) phenotype (CD4⁺/8^–/56^–), and only a minority of tumours express the CD8 (cytotoxic/suppressor) or CD56 (natural killer [NK]-associated) antigens. TIA-1 is a cytotoxic granule-associated protein expressed in NK cells and cytotoxic T lymphocytes (CTLs). Granzyme B, perforin and Fas ligand (FasL) are also expressed in activated CTLs and NK cells. To clarify the cytotoxic potential of ATLL cells, immunohistochemistry was performed in CD8⁺ and/or CD56⁺ ATLL cells, using anti-TIA-1, anti-granzyme B, anti-perforin and anti-FasL antibodies. We studied nine cases of CD8⁺ and/or CD56+ ATLL, all of which exhibited monoclonal integration of human T-cell leukaemia virus type 1 (HTLV-1) proviral DNA. Four cases exhibited a CD8⁺/CD56^– phenotype, four others had a CD8^–/CD56⁺ phenotype, and one was CD8⁺/CD56⁺. All but one case also expressed the surface antigens CD3, TCR αβ, and CD4. Expression of granzyme B and TIA-1 were demonstrated in three and two cases, respectively, but none expressed perforin or FasL. In the control study, 10 cases with typical CD3⁺/4⁺/8^–/56^– ATLL demonstrated no expression of those cytotoxic-associated proteins. Our findings suggest that CD8 and/or CD56 positivity probably confer(s) no cytotoxic function on ATLL cells, and it is possible that CD8 and CD56 may be simply aberrant surface markers in ATLL. Received: 20 January 1999 / Accepted: 13 April 1999     

B lymphocytes mediate Fas-dependent cytotoxicity in MRL/lpr mice

The Fas/Fas ligand (FasL) pathway is one of the two major effector mechanisms of T cell-mediated cytotoxicity. To prevent nonspecific killing by lymphoid cells, FasL expression on the cell surface of immune effector cells is strictly regulated. However, MRL/lpr autoimmune-prone mice massively overexpress FasL on their T lymphocytes, which render them able to kill Fas+ targets in vitro and in vivo. It is surprising that we show in the present work that B lymphocytes purified from MRL/lpr spleen cells express FasL to the same extent as T cells at the mRNA and protein level. These B cells are potent cytotoxic effectors against Fas+ but not Fas- targets. The B lymphocyte effectors were used ex vivo without any in vitro activation by B cell stimuli. Furthermore, we found that MRL/lpr B lymphocytes have the same cytotoxic potential as natural killer cells, which have been characterized as potent, Fas-mediated, cytotoxic effectors. The level of membrane-anchored FasL increases with the size of the B cell and cell-surface activation marker CD69 expression, indicating that the expression of FasL is up-regulated in parallel with the activation state of the B cell. The activated B cell population contained the major cytotoxic activity, and a minor part was associated with CD138/Syndecan-1+ plasma cells.     

Peritoneal natural killer cytotoxicity and CD25+CD3+ lymphocyte subpopulation are decreased in women with stage III-IV endometriosis

We examined the lymphocytes of peripheral blood (PB) and peritonealfluid (PF) of women with or without endometriosis to investigatethe alteration of cytotoxic activity of natural killer (NK)cells and activation of T cells in the peritoneal cavity ofwomen with endometriosis. A total 16 control women and 14 patientswith stage III–IV endometriosis were selected on the basisof laparoscopic examination in National Taiwan University Hospital.The lymphocyte subpopulations (B cell, NK cell and T cell),including T-cell activation markers (CD69, CD25, HLADR), inPB and PF were analysed by dual-colour flow cytometry. The NKcytotoxicity of PB and PF mononuclear cells was evaluated by⁵¹Cr release assay. There was significant decrease of NK cytotoxicityand CD25⁺CD3⁺lymphocyte subpopulation in PF of women with endometriosiscompared with those without endometriosis. However, there wasno difference in the proportion of NK cells in both PB and PFbetween women with and without endometriosis. Therefore, thedecreased NK cytotoxicity PF of women with endometriosis wasdue to the functional defect, but not quantitative defect, ofNK cells. The concomitant reduction of activated T cells inwomen with endometriosis might suggest its possible role inthe defect of NK cytotoxicity.     

CIK/NK细胞4周培养过程中的CD27、CD28的表达及其意义

目的:了解细胞因子诱导杀伤（CIK）细胞和自然杀伤（NK）细胞在培养过程中CD27和CD28的表达变化规律。方法:通过流式细胞仪检测CD3+CD56+ CIK细胞以及CD3-CD56+ NK细胞在4周培养过程中其上CD27和CD28的表达变化。结果:CD27在CIK和NK细胞上均于培养的第2周达到最高峰,分别为（44.57±4.07）％和（51.02±5.20）％,但之后逐步下降,在培养第4周降至30%左右的水平。CD28在CIK和NK细胞上分别是在第3周和第2周时达到表达的最高峰,为（4.40±0.66）％和（45.14±3.58）％,之后迅速下降,在培养第4周已经几乎消失。结论:根据CD27和CD28在CIK/NK细胞上的表达变化规律,CIK/NK细胞的收获时机以培养第3周为宜。     

U5 monoclonal antibody identifies a novel lymphocyte surface antigen preferentially expressed in human circulating natural killer cells with high cytotoxic activity

U5 monoclonal antibody (mAb), developed against Japanese monkey lymphocytes, identified a glycoprotein of 32 000 MW that is expressed in a subset of human circulating natural killer (NK) cells. The distribution of U5 molecules was restricted among CD16+ cells, and U5 antigen was preferentially expressed in the CD38+ subset. U5+ CD16+ CD56+ cells were highly active on NK assay against K562 target cells. Variations in cytolytic activities and mRNA expression of perforin, granzyme B and Fas ligand (FasL) were observed in U5- CD16+ CD56+ cells depending on the donor. We found that in some donors, a phenotypically mature (CD16+ CD56+) but functionally immature subset was present in the peripheral circulation. The U5- CD16+ CD56+ cells of some donors exhibited negligible cytolytic activity with no detectable expression of the above mRNAs, whereas those of the other donors had a significant but lower cytolytic activity with a reduced expression of granzyme B mRNA as compared with those of U5+ CD16+ CD56+ cells. Concanavalin A (Con A) stimulation induced an expression of U5 antigen in U5- CD16+ CD56+ cells accompanied by an up-regulation of granzyme B mRNA expression. These findings suggest that U5 antigen may be a novel molecule involved in the maturation or differentiation of human circulating NK cells.     

Accumulation of CD16-CD56+ natural killer cells with high affinity interleukin 2 receptors in human early pregnancy decidua.

Most human peripheral blood natural killer (NK) cells express the phenotype CD16+CD56+. However, a very minor subset of NK cells express CD16-CD56+, and these NK cells bear both interleukin 2 receptor (IL-2R)alpha (p55) and IL-2R beta (p75) (high affinity IL-2 receptors). In this report, we demonstrate that in human early pregnancy decidua--an interface between maternal immunocompetent cells and fetus (placenta)--abundant (approximately 83%) CD16-CD56+ NK cells with high affinity IL-2 receptors were present, and these cells responded to low amounts of IL-2 (4.5 pM). These CD16-CD56+ NK cells significantly expressed an early activation antigen, CD69, in vivo, whereas peripheral CD16-CD56+ NK cells did not express CD69. These findings suggest that CD16-CD56+ NK cells in early pregnancy decidua may be activated in vivo, and may play an important role in immunoregulation during early pregnancy. Also, decidual lymphocytes may be useful materials to study the mechanism of MHC-unrestricted cytotoxicity of this type of NK cells.     

Nasal T/NK cell lymphomas commonly express perforin and Fas ligand: important mediators of tissue damage

 

Aims:

Two molecular mechanisms of T/natural killer (NK) cell-mediated cytotoxicity, one perforin based and the other Fas based, have been demonstrated, and both systems induce cytotoxicity in the target cells. The Fas-based mechanism involves the transducing molecule Fas and its ligand (FasL). In addition, perforin and/or FasL are also expressed in the cytotoxic T/NK cells. This study was thus designed to investigate the Fas and perforin pathways of the cytotoxic T/NK lymphoma cells in the nasal cavity.  

Methods and results:

Eight patients with nasal lymphoma were analysed using immunohistochemical staining methods. Two cases were CD3+ CD56+ (T/NK cell) type, and six were CD3− CD56+ (NK cell) type. All cases showed Epstein–Barr virus genomes by in-situ hybridization. In addition, all cases showed the expression of TIA-1 (GMP-17), which is a marker of cytotoxic T and NK cells. FasL was expressed in the majority of the lymphoma cells and some histiocytes, while Fas was found in lymphoma cells and many non-neoplastic cells. In addition, the expression of perforin was detected in almost all lymphoma cells. In the double stainings, lymphoma cells expressed both FasL and perforin. Based on these findings, both the perforin- and Fas-based pathway of the cytotoxic T/NK lymphoma cells are thus considered to play an important role in the clinical features.  

Conclusions:

Tissue damage is a common morphological feature in nasal T/NK cell lymphoma. The above findings therefore support the theory that tissue damage is due to both the cytotoxicity of T/NK lymphoma cells as well as to angiocentricity.     

补肾中药对溴隐亭致流产鼠模型中蜕膜CD56~+NK细胞表面CD69和CD94表达的影响

为了观察补肾中药是否能影响蜕膜CD5 6 + NK细胞比例及其表面CD6 9、CD94的表达 ,从而进一步阐明补肾中药对母胎界面免疫的影响机制。SD大鼠于孕 6～ 8d皮下注射溴隐亭 0 3mg/kg·d ,建立改良的溴隐亭致SD大鼠流产模型 ,随机分为三组。A组为模型组 ;B、C组在孕 1～ 1 1d分别给予大剂量中药 (4 5g/kg·d)、P(8mg/kg·d) ,另设正常孕鼠对照 (D组 )。孕 1 2d处死 ,取蜕膜组织 ,分离成单个细胞悬液 ,用流式细胞分析技术观察 4组蜕膜CD5 6 + NK细胞的量及蜕膜NK细胞表面CD6 9、CD94的表达差异。结果发现 :B组 (P <0 0 5 )、C、D组 (P <0 0 1 )妊娠率与A组相比增加 ,并且有差异 ;B、C组蜕膜CD5 6 + NK细胞比例与A组相比明显增加 ,与D组无差异 ;各组蜕膜CD5 6 + NK细胞表面CD6 9表达无差异 ;B、C、D组CD94的表达与A组相比显著增加 ;A组蜕膜CD5 6 + NK细胞表达CD6 9与CD94相比明显增加 ,B、C组相反。因此 ,补肾中药能影响蜕膜CD5 6 + NK细胞表面CD6 9、CD94的表达 ,可能通过增加CD94的表达 ,抑制CD6 9从而进一步抑制NK细胞的活性 ,起到保胎作用     

CD40.FasL inhibits human T cells: evidence for an auto-inhibitory loop-back mechanism

A chimeric CD40.FasL (CD40-CD95L) protein was designed with the combined capacities to bind to two surface receptors on activated T cells, CD40 ligand (CD40L; CD154) and Fas receptor (CD95). CD40.FasL, once tethered to the cell surface via one of its ends, can transmit a signal via its other end. In principle, simultaneous triggering from both ends is possible, and thus there is the intriguing potential for 'auto-inhibition' if such dual triggering occurs on the same cell itself. Several lines of evidence support this mechanism: (i) CD40.FasL is cytotoxic to Fas receptor-positive cell lines of different cell lineages, (ii) CD40.FasL's function is potentiated when there is enforced expression of CD40L on target cells, (iii) CD40.FasL inhibition does not require intercellular contact, as demonstrated by soft agar clone formation and cell dilution analysis and (iv) introduction of exogenous CD40 into the system interferes with CD40.FasL inhibition. Taken together, these data are consistent with a 'loop-back' inhibitory mechanism within individual activated (CD40L and Fas receptor expressing) T cells causing suicide of these T cells. Significantly, this type of fusion protein provides a unique way to confine immunoinhibition to activated T cells.     

Clinicopathologic differences between 22 cases of CD56-negative and CD56-positive subcutaneous panniculitis-like lymphoma in Japan

CD56 is an important marker for prospecting clinicopathologic features of cytotoxic T-cell and natural killer (NK)/T-cell lymphomas. We examined 22 cases of subcutaneous panniculitis-like lymphoma and classified these into CD56-positive and CD56-negative groups. The 11 CD56-negative cases were mainly in the younger age group and had systemic subcutaneous nodules without ulceration. They exhibited subcutaneous invasion by medium-sized lymphoma cells, scattered erythrophagocytosis, patchy necrosis, and little tumor invasion in the superficial dermis. Their lymphoma cells had characteristics of CD3 epsilon-, CD8-, TcR beta F1-, T-cell intracellular antigen (TIA)1-, and granenzyme B-positive cytotoxic T cells and were negative for apoptosis-promoting proteins CD95 (Fas), Bax, CPP32 (caspase 3), and p53 (DO7). Ten patients were alive despite clinical signs of hemophagocytic syndrome and relapses in 7 cases. The 11 CD56-positive cases had systemic ulcerative skin tumors composed of pleomorphic lymphoma cells with massive necrosis and little erythrophagocytosis involving the subcutis and also often the whole dermis. Their tumor cells were positive for CD3 epsilon, TIA1, granenzyme B, CD95, CD95L (Fas ligand), Bax, and CPP32. Three cases were of the TcR beta F1-positive phenotype, 1 was of the TcR gamma/delta-positive T-cell phenotype, and 6 were of the TcR beta F1- and TcR gamma/delta-negative NK/T-cell phenotype. Six cases were p53 (DO7) positive. Seven cases had complications of liver dysfunction and cytopenia, and 8 died of disease. One CD56-negative case and 3 CD56-positive cases had nuclear signals of Epstein-Barr virus-encoded RNA in their lymphoma cells. The 2 groups had significantly (P <0.01) different prognoses by Kaplan-Meier and log-rank methods. Patients with CD56-negative and CD56-positive groups had statistically different clinicopathologic, immunohistologic, and functional findings and prognoses.     

乏氧对人外周血NK细胞NKG2A、NKG2D及CD44表达的影响

目的： 观察乏氧微环境对人外周血自然杀伤细胞(NK)表面自然杀伤细胞2族成员A(NKG2A)、自然杀伤细胞2族成员D(NKG2D)及CD44分子表达的影响,探讨乏氧抑制NK细胞杀伤活性的分子机制。方法: 采用密度梯度离心法分离健康人外周血单个核细胞（PBMC）,贴壁去除单核细胞获得外周血淋巴细胞（PBL）,分别置常氧（21％O2）、乏氧（1％O2）以及有或无人重组白细胞介素2(rhIL-2)（1×106 U/L）刺激条件下培养16 h,流式细胞术（FCM）检测不同 NK细胞亚群 NKG2A、NKG2D以及CD44分子的表达。结果: 常氧条件,人外周血CD3-CD56+NK细胞NKG2A、NKG2D表达的阳性率分别为16.16%和78.45%,乏氧条件下二者表达的阳性率分别为15.16%和71.08%;rhIL-2上调NKG2A和NKG2D的表达,乏氧不影响 rhIL-2对NKG2D、 NKG2A的上调作用;rhIL-2显著上调NK细胞CD44的表达,乏氧抑制CD44的表达（P<0.05）。结论: 乏氧下调外周血NK细胞表面受体NKG2D及CD44的表达,但对NKG2A的表达无显著影响。由此提示,NKG2D及CD44分子可能在乏氧引起的NK细胞杀伤活性抑制中具有重要作用。     

Killer inhibitory receptor CD158a overexpression among natural killer cells in women with endometriosis is undiminished by laparoscopic surgery and gonadotropin releasing hormone agonist treatment

PROBLEM: Natural killer (NK) dysfunction is considered to contribute to the pathogenesis of endometriosis. In this study, we investigated the host immune response to endometriosis in terms of killer inhibitory receptor (KIR) expression by NK cells. METHOD OF STUDY: We compared cells from Japanese women laparoscopically diagnosed with endometriosis and treated with laparoscopic surgery (n = 98), 1 month after laparoscopic surgery (n = 36), and 12 weeks after gonadotropin releasing hormone agonist (GnRHa) treatment (n = 18) to cells from 104 women with other laparoscopic diagnoses. KIR expression by NK cells was assessed in peripheral blood and peritoneal fluid samples by flow cytometry. RESULTS: In women with endometriosis, the percentage of CD158a-expressing cells among CD16-expressing NK (CD158a(+)NK) cells in both peritoneal fluid and peripheral blood was significantly higher than in control subjects. No significant differences in proportion of CD158a(+)NK cells were identified between peripheral blood NK cells sampled before and 1 month after laparoscopic surgery, or 12 weeks after initiating GnRHa treatment. CONCLUSIONS: Increased percentage of CD158a(+)NK cells in peripheral blood from women with endometriosis was undiminished by laparoscopic surgery and GnRHa treatment; the persistence of CD158a(+)NK cell excess is probably related to NK cell suppression in endometriosis. This overexpression may represent a risk factor for development of endometriosis and its recurrence after treatments.     

The Fas death pathway controls coordinated expansions of type 1 CD8 and type 2 CD4 T cells in Trypanosoma cruzi infection

We investigated the role of the Fas ligand (FasL)/Fas death pathway on apoptosis and cytokine production by T cells in Trypanosoma cruzi infection. Anti-FasL, but not anti-TNF-alpha or anti-TRAIL, blocked activation-induced cell death of CD8 T cells and increased secretion of IL-10 and IL-4 by CD4 T cells from T. cruzi-infected mice. CD4 and CD8 T cells up-regulated Fas/FasL expression during T. cruzi infection. However, Fas expression increased earlier in CD8 T cells, and a higher proportion of CD8 T cells was activated and expressed IFN-gamma compared with CD4 T cells. Injection of anti-FasL in infected mice reduced parasitemia and CD8 T cell apoptosis and increased the ratio of CD8:CD4 T cells recovered from spleen and peritoneum. FasL blockade increased the number of activated T cells, enhanced NO production, and reduced parasite loads in peritoneal macrophages. Injection of anti-FasL increased IFN-gamma secretion by splenocytes responding to T. cruzi antigens but also exacerbated production of type 2 cytokines IL-10 and IL-4 at a late stage of acute infection. These results indicate that the FasL/Fas death pathway regulates apoptosis and coordinated cytokine responses by type 1 CD8 and type 2 CD4 T cells in T. cruzi infection.