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免疫学杂志 2005年第11期
Although there is extensive indirect evidence suggesting that Bcl-x, a member of the antiapoptotic Bcl-2 gene family, is involved in T cell development and function, there is no direct evidence for its involvement. Zhang and He (p. 6967 ) used a targeting vector to develop a strain of mice whose T cells lacked mRNA and protein expression for all five isoforms of Bcl-x. The knockout mice had normal growth and development, but their spleens contained only 50–60% of mature CD4+ and CD8+ T lymphocytes seen in wild-type or heterozygous controls. In vitro proliferation and IL-2 production were comparable for knockout and control CFSE-labeled CD4+ or CD8+ T cells stimulated with anti-CD3 and/or anti-CD28 mAb; apoptosis induced by anti-CD3 plus anti-CD28 mAb and activation-induced T cell death induced by anti-CD3 mAb also were comparable. Bcl-2 levels before or after stimulation were only slightly different in knockout vs control CD4+ or CD8+ T lymphocytes. Primary CTL responses and anti-OVA activity and IFN- production in memory CTL responses were equivalent in knockout and control mice infected and challenged with Listeria monocytogenes expressing chicken OVA. Experimental and control mice produced comparable levels of IgG subtypes against DNP in mice immunized with DNP-KLH, and all mice immunized with SRBCs had identical Ab production and germinal center formation. The data indicate that effector and memory CD4+ and CD8+ T cell differentiation and function are normal in mice lacking Bcl-x and that CD28-mediated functions are independent of Bcl-x.
Ag-induced suppression of autoimmunity
Therapeutic expansion of Ag-specific T regulatory (Treg) cells could be a significant step toward control of autoimmunity. However, there are no well-defined approaches to accomplish that goal. Yu et al. (p. 6772 ) treated SJL/J mice, injected with proteolipid protein-1 peptide (PLP1)-specific TCR transgenic (Tg) T cells, with an aggregated Ig molecule carrying an encephalitogenic PLP1 peptide (agg Ig-PLP1). The Tg T cells had increased surface expression of CD25 and CTLA-4, Foxp3 mRNA expression, and IL-10 production compared with Tg T cells from untreated mice or from mice treated with soluble Ig-PLP1. Isolated agg Ig-PLP1-expanded Tg Treg cells inhibited PLP1-stimulated proliferation of CD25– Tg cells ex vivo. SJL/J mice injected with the expanded Tg Treg cells 3 days before PLP1 induction of experimental allergic encephalomyelitis (EAE) did not have the clinical relapses seen in untreated controls. Injection of expanded Tg Treg cells 1 day before EAE induction reduced the severity of the initial phase of the disease. Injection of expanded Tg Treg cells into RAG–/– SJL mice 1 day before transfer of naive Tg T cells protected them against the severe disease and death seen in recipients of naive Tg T cells alone; injection of anti-IL-10 mAb abrogated the EAE protection. Severity of EAE induced with a CNS homogenate was reduced by treatment with agg Igs carrying different myelin epitopes, and full severity was restored by prior treatment of recipients with anti-CD25 mAb. Transfer of agg Ig-PLP1-expanded Treg T cells protected recipients against EAE induced by PLP1, PLP2, or CNS homogenate, but not by a peptide from an unrelated myelin protein, but transfer of Tg Treg cells activated in vitro by PLP1-APC extended protection to EAE induced by unrelated myelin peptides. The results show that Ag-specific Treg activation can lead to broad suppression of EAE in mice.
Leptin influence on dendritic cells
Mice deficient for the hormone leptin, a member of the helical cytokine family, are not only obese but have impaired cell-mediated immune functions. Although leptin influences activities of several kinds of immune cells, its effect on dendritic cells (DC) has not been studied. Mattioli et al. (p. 6820 ) found that immature or mature human DC treated for 24 h with leptin up-regulated the leptin receptor mRNA and protein, increased STAT3 phosphorylation, increased production of IL-1, IL-6, and IL-12, and increased MIP-1 mRNA levels compared with untreated controls. Leptin treatment also down-regulated IL-8 mRNA and IL-10 secretion but did not induce phenotypic maturation. Only treated immature DC had up-regulated TNF- mRNA and secretion. Leptin-treated immature DC induced greater T cell proliferation in MLR than did untreated DC. Scanning electron microscopy showed uropod formation and ruffling on DC exposed to leptin for 24 h; polarization of F-actin filaments to uropods was detected by immunofluorescence. T cells stimulated in MLR with leptin-treated DC or culture supernatants were polarized toward a Th1 phenotype. Leptin treatment partially protected immature DC in vitro against spontaneous and UVB-induced apoptosis, increased levels of antiapoptotic Bcl-2 and Bcl-xL mRNAs, increased activation of NF-B subunits, and promoted the translocation of p65 NF-B to nuclei. The authors demonstrate that leptin plays a role in DC development, function, and survival.
Aspects of respiratory syncytial virus infection
There is no effective antiviral vaccine or treatment against respiratory syncytial virus (RSV), which causes severe lower respiratory disease and infects >90% of young children. As a first step to identifying potential targets for treatment, Arnold and K?nig (p. 7359 ) looked at early events in RSV infection. Infection of early passages of three types of human endothelial cells with live virus increased ICAM-1 mRNA and surface protein expression above constitutive background levels. Cells treated with pharmacological inhibitors of PI3K, ERK1/ERK2, protein kinase C, or p38 MAPK before and after viral infection showed diminished RSV-induced ICAM-1 up-regulation. More than twice as many PMA-activated promyelocytes or polymorphonuclear neutrophil granulocytes (PMN) bound to RSV-infected endothelial cells vs uninfected cells as measured by a leukocyte adhesion assay; cell binding was abolished by preincubation of the endothelial cells with an anti-ICAM-1 mAb. PMN transmigrated in an IL-8 gradient more rapidly across RSV-infected monolayers than across uninfected monolayers. A different approach to understanding RSV immunopathology, taken by Johnson et al. (p. 7234 ), examined the role of Th2 cytokines in the inflammatory response. Mice deficient in IFN-R, IFN-R, or IFN-R had RSV titers equivalent to those of wild-type mice 5 days after infection. Bronchoalveolar fluid from infected wild-type mice consisted primarily of monocytes/macrophages and lymphocytes, whereas that from all three infected mutant mouse strains had high levels of neutrophils. Eosinophils were detected in RSV-infected lungs of IFN-R–/– and IFN-R–/– mice, and IFN-R–/– and IFN-R–/– mice had limited CD8+ T cell expansion compared with the other infected groups. There was no IL-10 in supernatants of bronchoalveolar fluids from mice lacking both receptors, and the inflammatory response was eosinophilic compared with lymphocytic for the other strains. IFN- production of RSV peptide-stimulated immune splenocytes was abrogated by depletion of CD4+ T cells, but not CD8+ T cells. The first study suggests that RSV-infected endothelial cells are active participants in accumulation of PMN, whereas the second study highlights the importance of IFN- and IFN- in preventing an eosinophilic Th2 response to RSV infection.
Impact of SLE on EBV persistence
Infected B cells regulate persistent EBV infections in healthy individuals. Although patients with systemic lupus erythematosus (SLE) are known to have increased EBV titers in their blood and saliva, the origin of the increases is unknown. Gross et al. (p. 6599 ) found that frequencies of virus-infected cells were elevated 10-fold in the blood of 35 SLE patients compared with 44 healthy controls as measured by a limiting dilution EBV DNA PCR assay. The results were independent of patient age, number of B cells/milliliter of blood, or treatment with immunosuppressive medications. Frequencies of EBV-infected cells in 17 patients with other systemic autoimmune diseases were higher than in healthy individuals but significantly lower than in SLE patients; frequencies fluctuated with disease severity, being highest during disease flares. There was no correlation between virus-infected cell frequency and specific clinical or serologic markers. Expression of mRNA for EBV immediate-early lytic protein and latency membrane protein 1 was detected in 35 and 29%, respectively, of SLE patients’ blood but not in blood of healthy individuals; EBV latency membrane protein 2a also was expressed in SLE patients but rarely in controls. Nearly all of the virus-infected cells were IgD– memory B cells. Similar deregulation of another herpesvirus, CMV, did not occur in SLE patients. The authors conclude that the immune dysfunction of SLE disrupts the EBV persistent state and results in aberrant viral gene expression and increased frequency of infected B cells.
Loss of naive T cell diversity in the aged
Thymic involution begins at birth and results in an inability to generate new naive T cells after age 20–40 years. Although the total number of peripheral T cells and the proportion of naive and memory T cells remain fairly stable until 65 years of age, diversity of naive T cells with increasing age is unknown. Naylor et al. (p. 7446 ) measured TCR excision circles (TREC) to determine thymic output in healthy humans. Real-time PCR data showed that frequency and variability of TREC+ cells decreased progressively up to age 54, and then significantly declined further for age groups 55–69 and 70–90. However, the rapid proliferation of peripheral memory CD45RO+CD4+ T cells and slower proliferation of naive CD45RO–CD4+ T cells were fairly constant to age 70, after which increased cycling of both populations became significant. Receptor diversity of naive CD4+ T cells was measured by PCR amplification of unique TCR sequences. In individuals 25–30 and 60–65 years of age, 60% of all TCR sequences were below the level of detection, indicating great diversity; however, naive T cell repertoire diversity was reduced to 1% in individuals 75–80 years of age. TCR PCR products from a pool of naive CD4+ T cells hybridized 2-fold less intensely with other cell pools from the same individual in the 20–30 age group, whereas no differences in hybridization intensities were seen in different pools from the same individual in the 75–80 age group. Diversity in memory T cells in young adults through age 65 was constant, and then contracted dramatically. After age 75, diversities of naive and memory T cells were similar. The data demonstrate a severe loss of numbers and diversity of naive CD4+ T cells after age 65, even though the numbers of TREC+ cells had declined much earlier.
Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
EBV and Systemic Lupus Erythematosus: A New Perspective
Andrew J. Gross, Donna Hochberg, William M. Rand, and David A. Thorley-Lawson
The JI 2005 174: 6599-6607. [Abstract] [Full Text]
Specific T Regulatory Cells Display Broad Suppressive Functions against Experimental Allergic Encephalomyelitis upon Activation with Cognate Antigen
Ping Yu, Randal K. Gregg, J. Jeremiah Bell, Jason S. Ellis, Rohit Divekar, Hyun-Hee Lee, Renu Jain, Hanspeter Waldner, John C. Hardaway, Mary Collins, Vijay K. Kuchroo, and Habib Zaghouani
The JI 2005 174: 6772-6780. [Abstract] [Full Text]
Leptin Promotes Differentiation and Survival of Human Dendritic Cells and Licenses Them for Th1 Priming
Benedetta Mattioli, Elisabetta Straface, Maria Giovanna Quaranta, Luciana Giordani, and Marina Viora
The JI 2005 174: 6820-6828.
The Antiapoptotic Protein Bcl-xL Is Dispensable for the Development of Effector and Memory T Lymphocytes
Nu Zhang and You-Wen He
The JI 2005 174: 6967-6973.
Role for Innate IFNs in Determining Respiratory Syncytial Virus Immunopathology
Teresa R. Johnson, Sara E. Mertz, Negin Gitiban, Sue Hammond, Robin LeGallo, Russell K. Durbin, and Joan E. Durbin
The JI 2005 174: 7234-7241.
Respiratory Syncytial Virus Infection of Human Lung Endothelial Cells Enhances Selectively Intercellular Adhesion Molecule-1 Expression
Ralf Arnold and Wolfgang K?nig
The JI 2005 174: 7359-7367.
Influence of Age on T Cell Generation and TCR Diversity
Keith Naylor, Guangjin Li, Abbe N. Vallejo, Won-Woo Lee, Kerstin Koetz, Ewa Bryl, Jacek Witkowski, James Fulbright, Cornelia M. Weyand, and J?rg J. Goronzy
The JI 2005 174: 7446-7452.
Ag-induced suppression of autoimmunity
Therapeutic expansion of Ag-specific T regulatory (Treg) cells could be a significant step toward control of autoimmunity. However, there are no well-defined approaches to accomplish that goal. Yu et al. (p. 6772 ) treated SJL/J mice, injected with proteolipid protein-1 peptide (PLP1)-specific TCR transgenic (Tg) T cells, with an aggregated Ig molecule carrying an encephalitogenic PLP1 peptide (agg Ig-PLP1). The Tg T cells had increased surface expression of CD25 and CTLA-4, Foxp3 mRNA expression, and IL-10 production compared with Tg T cells from untreated mice or from mice treated with soluble Ig-PLP1. Isolated agg Ig-PLP1-expanded Tg Treg cells inhibited PLP1-stimulated proliferation of CD25– Tg cells ex vivo. SJL/J mice injected with the expanded Tg Treg cells 3 days before PLP1 induction of experimental allergic encephalomyelitis (EAE) did not have the clinical relapses seen in untreated controls. Injection of expanded Tg Treg cells 1 day before EAE induction reduced the severity of the initial phase of the disease. Injection of expanded Tg Treg cells into RAG–/– SJL mice 1 day before transfer of naive Tg T cells protected them against the severe disease and death seen in recipients of naive Tg T cells alone; injection of anti-IL-10 mAb abrogated the EAE protection. Severity of EAE induced with a CNS homogenate was reduced by treatment with agg Igs carrying different myelin epitopes, and full severity was restored by prior treatment of recipients with anti-CD25 mAb. Transfer of agg Ig-PLP1-expanded Treg T cells protected recipients against EAE induced by PLP1, PLP2, or CNS homogenate, but not by a peptide from an unrelated myelin protein, but transfer of Tg Treg cells activated in vitro by PLP1-APC extended protection to EAE induced by unrelated myelin peptides. The results show that Ag-specific Treg activation can lead to broad suppression of EAE in mice.
Leptin influence on dendritic cells
Mice deficient for the hormone leptin, a member of the helical cytokine family, are not only obese but have impaired cell-mediated immune functions. Although leptin influences activities of several kinds of immune cells, its effect on dendritic cells (DC) has not been studied. Mattioli et al. (p. 6820 ) found that immature or mature human DC treated for 24 h with leptin up-regulated the leptin receptor mRNA and protein, increased STAT3 phosphorylation, increased production of IL-1, IL-6, and IL-12, and increased MIP-1 mRNA levels compared with untreated controls. Leptin treatment also down-regulated IL-8 mRNA and IL-10 secretion but did not induce phenotypic maturation. Only treated immature DC had up-regulated TNF- mRNA and secretion. Leptin-treated immature DC induced greater T cell proliferation in MLR than did untreated DC. Scanning electron microscopy showed uropod formation and ruffling on DC exposed to leptin for 24 h; polarization of F-actin filaments to uropods was detected by immunofluorescence. T cells stimulated in MLR with leptin-treated DC or culture supernatants were polarized toward a Th1 phenotype. Leptin treatment partially protected immature DC in vitro against spontaneous and UVB-induced apoptosis, increased levels of antiapoptotic Bcl-2 and Bcl-xL mRNAs, increased activation of NF-B subunits, and promoted the translocation of p65 NF-B to nuclei. The authors demonstrate that leptin plays a role in DC development, function, and survival.
Aspects of respiratory syncytial virus infection
There is no effective antiviral vaccine or treatment against respiratory syncytial virus (RSV), which causes severe lower respiratory disease and infects >90% of young children. As a first step to identifying potential targets for treatment, Arnold and K?nig (p. 7359 ) looked at early events in RSV infection. Infection of early passages of three types of human endothelial cells with live virus increased ICAM-1 mRNA and surface protein expression above constitutive background levels. Cells treated with pharmacological inhibitors of PI3K, ERK1/ERK2, protein kinase C, or p38 MAPK before and after viral infection showed diminished RSV-induced ICAM-1 up-regulation. More than twice as many PMA-activated promyelocytes or polymorphonuclear neutrophil granulocytes (PMN) bound to RSV-infected endothelial cells vs uninfected cells as measured by a leukocyte adhesion assay; cell binding was abolished by preincubation of the endothelial cells with an anti-ICAM-1 mAb. PMN transmigrated in an IL-8 gradient more rapidly across RSV-infected monolayers than across uninfected monolayers. A different approach to understanding RSV immunopathology, taken by Johnson et al. (p. 7234 ), examined the role of Th2 cytokines in the inflammatory response. Mice deficient in IFN-R, IFN-R, or IFN-R had RSV titers equivalent to those of wild-type mice 5 days after infection. Bronchoalveolar fluid from infected wild-type mice consisted primarily of monocytes/macrophages and lymphocytes, whereas that from all three infected mutant mouse strains had high levels of neutrophils. Eosinophils were detected in RSV-infected lungs of IFN-R–/– and IFN-R–/– mice, and IFN-R–/– and IFN-R–/– mice had limited CD8+ T cell expansion compared with the other infected groups. There was no IL-10 in supernatants of bronchoalveolar fluids from mice lacking both receptors, and the inflammatory response was eosinophilic compared with lymphocytic for the other strains. IFN- production of RSV peptide-stimulated immune splenocytes was abrogated by depletion of CD4+ T cells, but not CD8+ T cells. The first study suggests that RSV-infected endothelial cells are active participants in accumulation of PMN, whereas the second study highlights the importance of IFN- and IFN- in preventing an eosinophilic Th2 response to RSV infection.
Impact of SLE on EBV persistence
Infected B cells regulate persistent EBV infections in healthy individuals. Although patients with systemic lupus erythematosus (SLE) are known to have increased EBV titers in their blood and saliva, the origin of the increases is unknown. Gross et al. (p. 6599 ) found that frequencies of virus-infected cells were elevated 10-fold in the blood of 35 SLE patients compared with 44 healthy controls as measured by a limiting dilution EBV DNA PCR assay. The results were independent of patient age, number of B cells/milliliter of blood, or treatment with immunosuppressive medications. Frequencies of EBV-infected cells in 17 patients with other systemic autoimmune diseases were higher than in healthy individuals but significantly lower than in SLE patients; frequencies fluctuated with disease severity, being highest during disease flares. There was no correlation between virus-infected cell frequency and specific clinical or serologic markers. Expression of mRNA for EBV immediate-early lytic protein and latency membrane protein 1 was detected in 35 and 29%, respectively, of SLE patients’ blood but not in blood of healthy individuals; EBV latency membrane protein 2a also was expressed in SLE patients but rarely in controls. Nearly all of the virus-infected cells were IgD– memory B cells. Similar deregulation of another herpesvirus, CMV, did not occur in SLE patients. The authors conclude that the immune dysfunction of SLE disrupts the EBV persistent state and results in aberrant viral gene expression and increased frequency of infected B cells.
Loss of naive T cell diversity in the aged
Thymic involution begins at birth and results in an inability to generate new naive T cells after age 20–40 years. Although the total number of peripheral T cells and the proportion of naive and memory T cells remain fairly stable until 65 years of age, diversity of naive T cells with increasing age is unknown. Naylor et al. (p. 7446 ) measured TCR excision circles (TREC) to determine thymic output in healthy humans. Real-time PCR data showed that frequency and variability of TREC+ cells decreased progressively up to age 54, and then significantly declined further for age groups 55–69 and 70–90. However, the rapid proliferation of peripheral memory CD45RO+CD4+ T cells and slower proliferation of naive CD45RO–CD4+ T cells were fairly constant to age 70, after which increased cycling of both populations became significant. Receptor diversity of naive CD4+ T cells was measured by PCR amplification of unique TCR sequences. In individuals 25–30 and 60–65 years of age, 60% of all TCR sequences were below the level of detection, indicating great diversity; however, naive T cell repertoire diversity was reduced to 1% in individuals 75–80 years of age. TCR PCR products from a pool of naive CD4+ T cells hybridized 2-fold less intensely with other cell pools from the same individual in the 20–30 age group, whereas no differences in hybridization intensities were seen in different pools from the same individual in the 75–80 age group. Diversity in memory T cells in young adults through age 65 was constant, and then contracted dramatically. After age 75, diversities of naive and memory T cells were similar. The data demonstrate a severe loss of numbers and diversity of naive CD4+ T cells after age 65, even though the numbers of TREC+ cells had declined much earlier.
Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
EBV and Systemic Lupus Erythematosus: A New Perspective
Andrew J. Gross, Donna Hochberg, William M. Rand, and David A. Thorley-Lawson
The JI 2005 174: 6599-6607. [Abstract] [Full Text]
Specific T Regulatory Cells Display Broad Suppressive Functions against Experimental Allergic Encephalomyelitis upon Activation with Cognate Antigen
Ping Yu, Randal K. Gregg, J. Jeremiah Bell, Jason S. Ellis, Rohit Divekar, Hyun-Hee Lee, Renu Jain, Hanspeter Waldner, John C. Hardaway, Mary Collins, Vijay K. Kuchroo, and Habib Zaghouani
The JI 2005 174: 6772-6780. [Abstract] [Full Text]
Leptin Promotes Differentiation and Survival of Human Dendritic Cells and Licenses Them for Th1 Priming
Benedetta Mattioli, Elisabetta Straface, Maria Giovanna Quaranta, Luciana Giordani, and Marina Viora
The JI 2005 174: 6820-6828.
The Antiapoptotic Protein Bcl-xL Is Dispensable for the Development of Effector and Memory T Lymphocytes
Nu Zhang and You-Wen He
The JI 2005 174: 6967-6973.
Role for Innate IFNs in Determining Respiratory Syncytial Virus Immunopathology
Teresa R. Johnson, Sara E. Mertz, Negin Gitiban, Sue Hammond, Robin LeGallo, Russell K. Durbin, and Joan E. Durbin
The JI 2005 174: 7234-7241.
Respiratory Syncytial Virus Infection of Human Lung Endothelial Cells Enhances Selectively Intercellular Adhesion Molecule-1 Expression
Ralf Arnold and Wolfgang K?nig
The JI 2005 174: 7359-7367.
Influence of Age on T Cell Generation and TCR Diversity
Keith Naylor, Guangjin Li, Abbe N. Vallejo, Won-Woo Lee, Kerstin Koetz, Ewa Bryl, Jacek Witkowski, James Fulbright, Cornelia M. Weyand, and J?rg J. Goronzy
The JI 2005 174: 7446-7452.