Interleukin 12-dependent interferon gamma production by CD8alpha+ lymphoid dendritic cells.

We investigated the role of antigen-presenting cells in early interferon (IFN)-gamma production in normal and recombinase activating gene 2-deficient (Rag-2(-/-)) mice in response to Listeria monocytogenes (LM) infection and interleukin (IL)-12 administration. Levels of serum IFN-gamma in Rag-2(-/-) mice were comparable to those of normal mice upon either LM infection or IL-12 injection. Depletion of natural killer (NK) cells by administration of anti-asialoGM1 antibodies had little effect on IFN-gamma levels in the sera of Rag-2(-/-) mice after LM infection or IL-12 injection. Incubation of splenocytes from NK cell-depleted Rag-2(-/-) mice with LM resulted in the production of IFN-gamma that was completely blocked by addition of anti-IL-12 antibodies. Both dendritic cells (DCs) and monocytes purified from splenocytes were capable of producing IFN-gamma when cultured in the presence of IL-12. Intracellular immunofluorescence analysis confirmed the IFN-gamma production from DCs. It was further shown that IFN-gamma was produced predominantly by CD8alpha+ lymphoid DCs rather than CD8alpha- myeloid DCs. Collectively, our data indicated that DCs are potent in producing IFN-gamma in response to IL-12 produced by bacterial infection and play an important role in innate immunity and subsequent T helper cell type 1 development in vivo.     

转录因子t-bet在人CD8+ T细胞和γδ T细胞干扰素-γ产生中的作用

目的:探讨转录因子t-bet对人CD8 T细胞和γδT细胞干扰素-γ(IFN-γ)产生的调控作用。方法:化学合成针对人t-bet基因的小干扰RNA(siRNA),转染体外培养的人γδT细胞和αβT细胞,利用流式细胞仪分选纯化CD8 T细胞和δγT细胞,半定量RT-PCR检测CD8 T细胞和γδT细胞中t-bet mRNA的表达变化,流式细胞术检测转染前后IFN-γ产生的变化情况。结果:转染siRNA后的人CD8 T细胞和γδT细胞t-bet mRNA表达强度分别为(24.75±1.18)%和(25.28±1.04)%,较转染前明显减小(P<0.05);在t-bet表达受到抑制的同时,γδT细胞中IFN-γ 细胞为(56.57±6.67)%,与错义序列组比较差异有显著性(P<0.05)。结论:siRNA可有效降低人CD8 T细胞和γδT细胞t-bet的基因表达,转录因子t-bet在γδT细胞IFN-γ产生中所起的作用与CD8 T细胞不完全相同。     

Genetic engineering of murine CD8+ and CD4+ T cells for preclinical adoptive immunotherapy studies

T-cell receptor (TCR) gene therapy enables for the rapid creation of antigen-specific T cells from mice of any strain and represents a valuable tool for preclinical immunotherapy studies. Here, we describe the superiority of γ-retroviral vectors compared with lentiviral vectors for transduction of murine T cells and surprisingly illustrate robust gene-transfer into phenotypically naive/memory-stem cell like (TN/TSCM; CD62L(hi)/CD44(low)) and central memory (TCM; CD62L(hi)/CD44(hi)) CD8+ T cells using murine stem cell-based γ-retroviral vectors (MSGV1). We created MSGV1 vectors for a major histocompatibility complex-class I-restricted TCR specific for the melanocyte-differentiation antigen, glycoprotein 100 (MSGV1-pmel-1), and a major histocompatibility complex-class II-restricted TCR specific for tyrosinase-related protein-1 (MSGV1-TRP-1), and found that robust gene expression required codon optimization of TCR sequences for the pmel-1 TCR. To test for functionality, we adoptively transferred TCR-engineered T cells into mice bearing B16 melanomas and observed delayed growth of established tumors with pmel-1 TCR engineered CD8+ T cells and significant tumor regression with TRP-1 TCR transduced CD4 T cells. We simultaneously created lentiviral vectors encoding the pmel-1 TCR, but found that these vectors mediated low TCR expression in murine T cells, but robust gene expression in other murine and human cell lines. These results indicate that preclinical murine models of adoptive immunotherapies are more practical using γ-retroviral rather than lentiviral vectors.     

IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells

Lymphopenia is a serious consequence of HIV infection and the administration of cancer chemotherapeutic agents. Although growth factors can be administered to patients to increase circulating neutrophils, there is no effective method to stimulate CD8+ lymphocyte production in humans, in vivo. This report is the first to describe the administration of recombinant interleukin-7 to humans and demonstrates the ability of this cytokine to mediate selective increases in CD4+ and CD8+ lymphocytes along with a decrease in the percentage of CD4+ T-regulatory cells. These studies suggest an important role for interleukin-7 in the treatment of patients with lymphopenia.     

On the role of CD4+ T cells in the CD8+ T-cell response elicited by recombinant adenovirus vaccines.

We have investigated the role of CD4(+) T cells in the development of the CD8(+) T-cell response after immunization with recombinant adenovirus (rAd). In the absence of CD4(+) T cells, the "unhelped" CD8(+) T-cell population exhibited a reduction in primary expansion and long-term survival that appeared to be due to inadequate priming of na?ve T cells. There were few functional or phenotypic differences between the helped and unhelped CD8(+) T-cell populations with the exception of O-glycosylated CD43, a marker of effector cells, which was augmented on the unhelped CD8(+) T-cell population. In some cases, the unhelped CD8(+) T-cell population exhibited reduced ability to control virus infection; however, this appeared to be a function of the reduced frequency of antigen-specific CD8(+) T cells. Most notably, the unhelped CD8(+) T-cell population exhibited no defect in secondary expansion. These results provide insight into the role of CD4(+) T cells during the primary CD8(+) T-cell response generated by rAd vaccines and identify potential benefits and issues that must be considered when using adenovirus vaccines under conditions where CD4(+) T-cell function may be limiting, such as vaccination of human immunodeficiency virus patients.     

Immunity to a pulmonary Cryptococcus neoformans infection requires both CD4+ and CD8+ T cells

The role of CD4+ and CD8+ T cells in mediating pulmonary clearance of a cryptococcal infection was investigated. Intratracheal inoculation of BALB/c and C.B-17 mice with a moderately virulent strain of Cryptococcus neoformans (52D) resulted in a pulmonary infection, which was cleared by a T cell-dependent mechanism. During this clearance, there was a significant influx of both CD4+ and CD8+ T cells into the lungs. Depletion of CD4+ T cells by injections of CD4-specific monoclonal antibody (mAb) prevented pulmonary clearance and also resulted in significant colonization of the brain and spleen of infected mice. CD4 depletion did not prevent the influx of CD8+ T cells into the lungs. Surprisingly, depletion of CD8+ T cells by mAb also ablated pulmonary clearance. CD8-depleted mice also had a small but significant increase in brain and spleen colony-forming unit compared to control mice by the end of the study. CD4+ T cell pulmonary influx was independent of the presence of CD8+ T cells. The lungs of T cell-depleted mice were examined histologically. CD4+ and CD8+ T cells each mediated a degree of inflammatory influx seen in the lungs of infected mice and raised the possibility that CD4+ and CD8+ T cells may synergize to generate the inflammatory response in the lungs. Numerous phagocytized but intact cryptococci were seen in the inflammatory foci of CD8-depleted mice but not in control or CD4-depleted mice. We propose that CD4+ T cells may recruit and activate effector phagocytes while CD8+ T cells predominantly function to lyse cryptococcus-laden unactivated phagocytes similar to the function of CD8+ T cells during listeria and mycobacteria infections.     

CRTAM controls residency of gut CD4+CD8+ T cells in the steady state and maintenance of gut CD4+ Th17 during parasitic infection

Retention of lymphocytes in the intestinal mucosa requires specialized chemokine receptors and adhesion molecules. We find that both CD4⁺CD8⁺ and CD4⁺ T cells in the intestinal epithelium, as well as CD8⁺ T cells in the intestinal mucosa and mesenteric lymph nodes, express the cell adhesion molecule class I–restricted T cell–associated molecule (Crtam) upon activation, whereas the ligand of Crtam, cell adhesion molecule 1 (Cadm1), is expressed on gut CD103⁺DCs. Lack of Crtam–Cadm1 interactions in Crtam^−/− and Cadm1^−/− mice results in loss of CD4⁺CD8⁺ T cells, which arise from mucosal CD4⁺ T cells that acquire a CD8 lineage expression profile. After acute oral infection with Toxoplasma gondii, both WT and Crtam^−/− mice mounted a robust TH1 response, but markedly fewer TH17 cells were present in the intestinal mucosa of Crtam^−/− mice. The almost exclusive TH1 response in Crtam^−/− mice resulted in more efficient control of intestinal T. gondii infection. Thus, Crtam–Cadm1 interactions have a major impact on the residency and maintenance of CD4⁺CD8⁺ T cells in the gut mucosa in the steady state. During pathogenic infection, Crtam–Cadm1 interactions regulate the dynamic equilibrium between newly formed CD4⁺ T cells and their retention in the gut, thereby shaping representation of disparate CD4⁺ T cell subsets and the overall quality of the CD4⁺ T cell response.Class I–restricted T cell–associated molecule (Crtam) is an Ig-like cell surface protein that was originally found on activated NKT cells (Kennedy et al., 2000), NK cells, and CD8⁺ T cells (Arase et al., 2005; Boles et al., 2005; Galibert et al., 2005) and shown to bind the cell adhesion molecule 1 (Cadm1, also known as Nectin like [Necl] 2; Arase et al., 2005; Boles et al., 2005; Galibert et al., 2005). Cadm1 is a cell surface molecule of the nectin and Necl families that is expressed on CD8α DCs (Galibert et al., 2005; Poulin et al., 2010), epithelial cells, neurons, and tumor cells (Sakisaka and Takai, 2004; Mizutani et al., 2011). Crtam–Cadm1 interactions strengthen NK cell and CD8⁺ T cell effector functions (Arase et al., 2005; Boles et al., 2005; Galibert et al., 2005; Murakami, 2005) and promote the retention of virus-specific CD8⁺ T cells within LNs (Takeuchi et al., 2009). One report proposed that Crtam is essential for the establishment of CD4⁺ T cell polarization after TCR engagement, a process which blocks CD4⁺ T cell division and induces the capacity to secrete IFN-γ, IL-17, and IL-22 (Yeh et al., 2008).The immune system associated with the gastrointestinal mucosa comprises large numbers of dispersed lymphoid cells that reside in the epithelium and the underlying lamina propria. Intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) include antigen-experienced CD8⁺ and CD4⁺ T cells, γδ T cells, various subsets of innate lymphoid cells (ILCs), and IgA-secreting plasma cells (Jabri and Ebert, 2007; Cerutti, 2008; Cheroutre et al., 2011; Sheridan and Lefrançois, 2011; Spits et al., 2013). Homing and residency of IELs and LPLs in the mucosa requires specialized chemokine receptors, such as CCR9, CCR6, and CXCR6, which detect chemokines released by gut epithelial cells (CCL25, CCL20, and CXCL16, respectively; Johansson-Lindbom and Agace, 2007). Integrins, like CD103 (α_E) and α₄β₇, also play an essential role in promoting homing and retention of IELs and LPLs in the mucosa by binding E-cadherin and MAdCAM-1 on epithelial cells and vascular endothelial cells, respectively (Johansson-Lindbom and Agace, 2007).T cell acquisition of homing and adhesion molecules is induced by T cell interaction with DCs (Mora et al., 2008; Villablanca et al., 2011). Among the disparate subsets of DC in the intestinal lamina propria and mesenteric LNs (mLN), the CD103⁺ DC subset produces retinoic acid (RA), which induces the gut homing receptors CCR9 and α₄β₇ on lymphocytes (Coombes et al., 2007; Mora et al., 2008; Villablanca et al., 2011). Gut-associated CD103⁺ DCs also produce TGF-β, which induces the expression of CD103 on T cells (Coombes et al., 2007; Mora et al., 2008; Villablanca et al., 2011). In addition to imprinting gut-homing capacity on T cells, gut CD103⁺ DCs control the differentiation of CD4⁺ T cells by priming regulatory CD4⁺ T cells during the steady state (Mucida et al., 2007) and TH1 and TH17 cells during inflammation (DePaolo et al., 2011; Hall et al., 2011).Here, we investigated the impact of Crtam–Cadm1 interaction in the intestinal immune system. We find that Crtam is expressed upon activation on all CD8⁺ T cells of the intestinal mucosa and mLN, intraepithelial CD4⁺ T cells, and intraepithelial CD4⁺CD8⁺ T cells, whereas Cadm1 is expressed on gut CD103⁺ DCs. Crtam–Cadm1 interactions have a major impact on the maintenance of intraepithelial CD4⁺CD8⁺ T cells and a limited influence on the presence of mucosal CD4⁺ and CD8⁺ T cells. Crtam^−/− and Cadm1^−/− mice almost completely lacked CD4⁺CD8⁺ T cells in the intestinal epithelium under steady-state conditions and had fewer CD4⁺ and CD8⁺ T cells in the intestinal mucosa than WT mice. CD4⁺CD8⁺ T cells arise from CD4⁺ T cells that acquire a CD8 T cell lineage gene expression profile upon reaching the intestinal mucosa (Mucida et al., 2013; Reis et al., 2013). Therefore, we further investigated the role of Crtam–Cadm1 interactions in governing CD4⁺ T cell homing and maintenance in the intestinal mucosa, and found that Crtam^−/− CD4⁺ T cells reconstituted the intestinal CD4⁺ T cell and CD4⁺CD8⁺ T cell subsets less effectively than did WT CD4⁺ T cells after transfer into Rag1^−/− mice. Moreover, fewer intestinal CD4⁺ T cells in Crtam^−/− mice expressed gut homing, adhesion, and retention molecules typical of their counterparts in WT mice (including CCR9, CD103, and CD69), and hence adhered less firmly to the intestinal mucosa.Crtam deficiency did not affect the intrinsic capacity of naive CD4⁺ T cells to differentiate into IFN-γ– or IL-17–producing CD4⁺ T cells in vitro. After acute oral infection with Toxoplasma gondii, both WT and Crtam^−/− mice mounted a robust TH1 response and cleared the intestinal infection. However, a preferential reduction of TH17 cells was evident within the intestinal mucosa CD4⁺ T cells in the Crtam^−/− mice. The almost exclusive TH1 response in Crtam^−/− mice resulted in more efficient clearance of intestinal infection. Antibody blockade of IL-17 in WT mice orally infected with T. gondii recapitulated the enhanced host response of Crtam^−/− mice. Thus, the defects in T cell gut homing and maintenance in Crtam^−/− mice preferentially affected TH17, whereas TH1 were relatively unaffected. Because the differentiation of CD4⁺CD8⁺ T cells from CD4⁺ T cells skews CD4⁺ T cell cytokine production toward IFN-γ at the expenses of IL-17 production (Mucida et al., 2013; Reis et al., 2013), the need for continuous replacement of lost CD4⁺CD8⁺ T cells in Crtam^−/− mice may result in a relative depletion of TH17 cells. Together, these results demonstrate that Crtam–Cadm1 interactions have a major impact on the residency and maintenance of CD4⁺CD8⁺ T cells in the gut mucosa in the steady-state. During mucosal responses against pathogenic infection, Crtam–Cadm1 interactions may be required to retain a balanced representation of disparate CD4⁺ T cell subsets, thereby influencing the overall quality of the CD4⁺ T cell response.     

Enhanced production of murine interferon gamma by T cells generated in response to bacterial infection

Spleen cell cultures derived from animals infected 6 d earlier with Listeria monocytogenes produced 10-20-fold more murine interferon gamma (MuIFN gamma) than spleen cells from nonimmune mice in response to stimulation with T cell mitogens. A striking temporal association was found between the enhanced synthesis of MuIFN gamma and the development of anti-Listeria immunity in that both the potential for increased MuIFN gamma production and the generation of Listeria-protective T cells developed and then decayed in unison. Treatment of spleen cells with monoclonal anti-Thy-1.2 plus complement virtually abolished the ability of cells from Listeria-immune mice to synthesize MuIFN gamma. The T cells producing MuIFN gamma were found to be more susceptible to complement-mediated lysis with monoclonal anti-Lyt-1.2 than with monoclonal anti-Lyt-2.2. The production of MuIFN gamma was not affected by treating spleen cells with anti-IgG antisera or with a monoclonal antibody directed against I-A specificities. MuIFN gamma was detected 4 h after the beginning of mitogenic stimulation of spleen cell cultures, and peak levels of MuIFN gamma were reached by 18 h. The IFN synthesized by mitogen-induced spleen cells derived from Listeria-immune mice were relatively labile at pH 2.0 and neutralized by a rabbit anti-MuIFN gamma serum but not by an antiserum having specificities for MuIFN alpha and MuIFN beta. The apparent molecular weight of the MuIFN gamma, as estimated by molecular sieving on a Bio-gel P-60 column, was estimated to be 38,000, and the isoelectric point as determined by chromatofocusing was extremely heterogeneous, ranging between pH 5.0 and pH 7.0.     

SARS-CoV-2 breakthrough infection in vaccinees induces virus-specific nasal-resident CD8+ and CD4+ T cells of broad specificity

Rapid recognition of SARS-CoV-2–infected cells by resident T cells in the upper airway might provide an important layer of protection against COVID-19. Whether parenteral SARS-CoV-2 vaccination or infection induces nasal-resident T cells specific for distinct SARS-CoV-2 proteins is unknown. We isolated T cells from the nasal mucosa of COVID-19 vaccinees who either experienced SARS-CoV-2 infection after vaccination (n = 34) or not (n = 16) and analyzed their phenotype, SARS-CoV-2 specificity, function, and persistence. Nasal-resident SARS-CoV-2–specific CD8⁺ and CD4⁺ T cells were detected almost exclusively in vaccinees who experienced SARS-CoV-2 breakthrough infection. Importantly, the Spike-specific T cells primed by vaccination did not suppress the induction of T cells specific for other SARS-CoV-2 proteins. The nasal-resident T cell responses persisted for ≥140 d, with minimal sign of waning. These data highlight the importance of viral nasal challenge in the formation of SARS-CoV-2–specific antiviral immunity at the site of primary infection and further define the immunological features of SARS-CoV-2 hybrid immunity.     

A gammaherpesvirus-secreted activator of Vbeta4+ CD8+ T cells regulates chronic infection and immunopathology

Little is known about herpesvirus modulation of T cell activation in latently infected individuals or the implications of such for chronic immune disorders. Murine gammaherpesvirus 68 (MHV68) elicits persistent activation of CD8(+) T cells bearing a Vbeta4(+) T cell receptor (TCR) by a completely unknown mechanism. We show that a novel MHV68 protein encoded by the M1 gene is responsible for Vbeta4(+) CD8(+) T cell stimulation in a manner reminiscent of a viral superantigen. During infection, M1 expression induces a Vbeta4(+) effector T cell response that resists functional exhaustion and appears to suppress virus reactivation from peritoneal cells by means of long-term interferon-gamma (IFNgamma) production. Mice lacking an IFNgamma receptor (IFNgammaR(-/-)) fail to control MHV68 replication, and Vbeta4(+) and CD8(+) T cell activation by M1 instead contributes to severe inflammation and multiorgan fibrotic disease. Thus, M1 manipulates the host CD8(+) T cell response in a manner that facilitates latent infection in an immunocompetent setting, but promotes disease during a dysregulated immune response. Identification of a viral pathogenecity determinant with superantigen-like activity for CD8(+) T cells broadens the known repertoire of viral immunomodulatory molecules, and its function illustrates the delicate balance achieved between persistent viruses and the host immune response.     

Contribution of CD4+, CD8+CD28+, and CD8+CD28- T cells to CD3+ lymphocyte homeostasis during the natural course of HIV-1 infection.

The relationship between the number of circulating CD4+ T cells and the presence of particular CD8+ T cell subsets was analyzed by flow cytometry on PBL from asymptomatic HIV-1-infected patients whose specimens were collected every 2 mo for a total period of 32 mo. Only slight variations were detected in the absolute number of lymphocytes and percentage of CD3+ lymphocytes, whereas both CD4+ and CD8+ T cell subsets showed wide intrapatient variation. Variations in the number of CD8+CD28+ cells paralleled those of the CD4+ T cell subset in each patient tested, while the presence of CD8+CD28- T cells correlated inversely with CD4+ and CD8+CD28+ T cells. These data show that changes in the number of circulating CD4+-and CD8+CD28+ T cells are strongly related to the presence of CD8+CD28- T cells in these patients. Insight into the significance of CD8+CD28- T cell expansion will allow us to understand the mechanisms and significance of the HIV-1- driven change in CD4+CD8+ T cell homeostasis and the basic immunopathology of HIV disease.     

Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration

The regulation of tolerance to self-proteins and the suppression of T-cell responses have in part been attributed to the activity of CD25+CD4+ T regulatory (Treg) cells. Further, Treg cells can inhibit the antitumor effectiveness of adoptive immunotherapy and active immunization approaches in preclinical models. In an effort to selectively eliminate Treg cells from human peripheral blood mononuclear cell to potentially bolster antitumor responses, we have evaluated the Treg-cell depleting capacity of the CD25-directed immunotoxin, RFT5-SMPT-dgA. In preclinical studies, incubation of human peripheral blood mononuclear cell with RFT5-SMPT-dgA mediated a partial reduction in the levels of CD25+, Foxp3-expressing CD4+ T cells in vitro. Administration of RFT5-SMPT-dgA to 6 patients with metastatic melanoma induced a transient but robust reduction in the number of CD25high CD4 T cells in vivo (a 97.5% mean reduction at nadir; from 69.4 +/- 12.4 cells/miroL to 1.7 +/- 0.3 cells/microL). The reduction in FOXP3+ CD4 T-cell number was less comprehensive (a 71.3% mean reduction at nadir; from 66.6 +/- 16.5 cells/microL to 14.2 +/- 3.9 cells/tL). This resulted in the selective persistence of a stable number of CD25(low/neg) FOXP3+ CD4+ T cells in vivo. No objective antitumor responses were seen in any patient. Our results indicate that the CD25-directed, RFT5-SMPT-dgA immunotoxin can mediate a transient, partial reduction in Treg-cell frequency and number in vitro and in vivo and suggest that comprehensive eradication of human Treg cells in vivo may require the ability to target and eliminate FOXP3+ CD4+ T cells expressing both high and low levels of CD25.     

CD4+ but not CD8+ cells are essential for allorejection

The generation of knockout mice with targeted gene disruption has provided a valuable tool for studying the immune response. Here we describe the use of CD4 and CD8 knockout mice to examine the role of CD4+ and CD8+ cells in initiating allotransplantation rejection. Pretreatment with a brief course of depletive anti-CD4 monoclonal antibody therapy allowed permanent survival of heart, but not skin, allografts transplanted across a major histocompatibility barrier. However, skin as well as heart grafts were permanently accepted in the CD4 knockout mice. Transfer of CD4+ cells into CD4 knockout recipient mice 1 d before skin engraftment reconstituted rejection, demonstrating that CD4+ cells are necessary for initiating rejection of allogeneic transplants. Major histocompatibility complex disparate heart and skin allografts transplanted into CD8 knockout recipients were rejected within 10 d. This study demonstrates that CD4+ but not CD8+ T cells are absolutely required to initiate allograft rejection.     

Induction of Fc epsilon R2/CD23 on human epidermal Langerhans cells by human recombinant interleukin 4 and gamma interferon

Human rIL-4 and human rIFN-gamma are able to induce the expression of the low affinity receptor for IgE (Fc epsilon R2/CD23) on normal human epidermal Langerhans cells, whereas IL-2 and PMA have no effect. A synergistic effect is observed when both cytokines are combined. These receptors are synthesized de novo by the LC since cycloheximide completely inhibits the appearance of Fc epsilon R2/CD23. Fc epsilon R2/CD23+ LC may have a major role in the pathogenesis of atopic eczema, as well as in the regulation of IgE synthesis.     

Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses

CD4+ T cell help is important for the generation of CD8+ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell responses markedly enlarged the population size of antigen-specific CD8+ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8+ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions. Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response. Down-modulation of CD8+ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.     

Prostaglandin E2 selectively increases interferon gamma receptor expression on human CD8+ lymphocytes.

We previously reported that prostaglandin E2 (PGE2) at a physiologic concentration (10(-8) M) and interferon gamma (IFN gamma), acting sequentially, were required for the differentiation of suppressor cells in mitogen-stimulated cultures. The present study was designed to test whether PGE2 might mediate IFN gamma-dependent effects on CD8+ cells by altering the number and/or affinity of their IFN gamma receptors. CD8+ and CD4+ cells when cultured for 18 h expressed comparable numbers of IFN gamma receptors of a single high affinity. Incubation with 10(-8) M PGE2 for 18 h, however, increased the number of IFN gamma receptors on CD8+ cells without affecting the binding affinity. Similar effects were not observed with CD4+ cells, nor when CD8+ cells were cultured in 10(-8) M PGD2. Concentrations of PGE2, which were ineffective in the induction of IFN gamma-dependent suppressor cell differentiation, also did not affect IFN gamma receptor expression on CD8+ cells. This observation of a specific stimulatory effect of PGE2 on the display of IFN gamma receptors of CD8+ cells suggests a novel mechanism for eicosanoid function through tissue-specific regulation of hormone receptors.     

CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses

Naturally occurring CD4+CD25+ regulatory T cells appear important to prevent activation of autoreactive T cells. This article demonstrates that the magnitude of a CD8+ T cell-mediated immune response to an acute viral infection is also subject to control by CD4+CD25+ T regulatory cells (Treg). Accordingly, if natural Treg were depleted with specific anti-CD25 antibody before infection with HSV, the resultant CD8+ T cell response to the immunodominant peptide SSIEFARL was significantly enhanced. This was shown by several in vitro measures of CD8+ T cell reactivity and by assays that directly determine CD8+ T cell function, such as proliferation and cytotoxicity in vivo. The enhanced responsiveness in CD25-depleted animals was between three- and fourfold with the effect evident both in the acute and memory phases of the immune response. Surprisingly, HSV infection resulted in enhanced Treg function with such cells able to suppress CD8+ T cell responses to both viral and unrelated antigens. Our results are discussed both in term of how viral infection might temporarily diminish immunity to other infectious agents and their application to vaccines. Thus, controlling suppressor effects at the time of vaccination could result in more effective immunity.     

供体凋亡淋巴细胞预输注对猪肝移植受体CD4+T、CD8+T、CD4+CD25+调节性T细胞的影响

背景:凋亡细胞能够主动调节机体的免疫功能,并能通过调节机体细胞免疫和体液免疫的途径诱导免疫耐受,但这些结果只在大鼠肝脏移植模型中证实.目的:探讨通过60Co γ射线体外处理后的供体淋巴细胞预输注诱导猪肝移植特异性免疫耐受的作用中,对淋巴细胞亚群的影响.方法:建立非转流小型猪原位肝移植模型.将受体猪随机摸球法均分为2 组:空白对照组,受体猪无特殊处理,行肝移植;淋巴细胞组:受体猪在肝移植前7 d 经耳静脉注射60Co γ射线处理过的5×108 个供体淋巴细胞.观察两组受体猪移植后的存活时间,移植后T 淋巴细胞亚型CD4+T、CD8+T、CD4+CD25+Tr 变化及病理.结果与结论:移植后3 d,两组病理活检均呈急性中、重度排斥反应;移植后6 d,两组均呈急性重度排斥反应.移植后1,3,6 d CD4+T、CD8+T、CD4+CD25+Tr 升降趋势,两组间差异无显著意义(P ＞ 0.05).提示,60Co γ射线体外处理过的淋巴细胞预输注未能够诱导猪同种异体肝移植特异性免疫耐受,未能引起T 淋巴细胞亚群变化有关.