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Fabrina Gaspal,
David Withers,
Manoj Saini,
Vasileios Bekiaris,
Fiona M McConnell,
Andrea White,
Mahmood Khan,
Hideo Yagita,
Lucy S K Walker,
Graham Anderson,
Peter J L Lane
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ABSTRACT: Our previous studies have implicated signaling through the tumor necrosis family receptors OX40 and CD30 as critical for maintaining CD4 memory responses. We show that signals through both molecules are also required for CD4 effector-mediated autoimmune tissue damage. Under normal circumstances, male mice deficient in the forkhead transcription factor FoxP3, which lack regulatory CD4 T cells, develop lethal autoimmune disease in the first few weeks of life. However, in the combined absence of OX40 and CD30, FoxP3-deficient mice develop normally and breed successfully. The extensive tissue infiltration and organ destruction characteristic of FoxP3 disease does not appear in these mice, and their mortality is not associated with autoimmunity. Although the absence of OX40 plays the dominant role, FoxP3-deficient mice sufficient in CD30 but deficient in OX40 signals still eventually develop lethal disease. This result was supported by the observation that blocking antibodies to OX40 and CD30 ligands also abrogated disease mediated by FoxP3-deficient T cells. These observations identify OX40 and CD30 signals as essential for the development of clinically relevant CD4-dependent autoimmunity and suggest that combination therapies that abrogate these signals might be used to treat established human autoimmune diseases.
Journal of Experimental Medicine 08/2011; 208(8):1579-84. · 13.85 Impact Factor
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Soochan Kim,
Sinsuk Han,
David R. Withers, Fabrina Gaspal,
Jingyu Bae,
Song Baik,
Hyun-Chool Shin,
Kyung-Su Kim,
Vasileios Bekiaris,
Graham Anderson,
Peter Lane,
Mi-Yeon Kim
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ABSTRACT: Here, we identify cells within human adult secondary lymphoid tissues that are comparable in phenotype and location to the lymphoid tissue inducer (LTi) cells that persist in the adult mouse. Identified as CD117+CD3−CD56− cells, like murine LTi cells, they lack expression of many common lineage markers and express CD127, OX40L and TRANCE. These cells were detected at the interface between the B- and T- zones, as well as at the subcapsular sinus in LNs, the location where LTi cells reside in murine spleen and LNs. Furthermore, like murine LTi cells, these cells expressed high levels of IL-22 and upregulated IL-22 expression upon IL-23 stimulation. Importantly, these cells were not an NK cell subset since they showed no expression of IFN-γ and perforin. Interestingly, a subset of the CD117+CD3−CD56−OX40L+ population expressed NKp46, again similar to recent findings in mice. Finally, these cells supported memory CD4+ T-cell survival in an OX40L-dependent manner. Combined, these data indicate that the CD117+CD3−CD56−OX40L+ cells in human secondary lymphoid tissues are comparable in phenotype, location and function to the LTi cells that persist within adult murine secondary lymphoid tissues.
European Journal of Immunology 05/2011; 41(6):1563 - 1572. · 5.10 Impact Factor
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Soochan Kim,
Sinsuk Han,
David R Withers, Fabrina Gaspal,
Jingyu Bae,
Song Baik,
Hyun-Chool Shin,
Kyung-Su Kim,
Vasileios Bekiaris,
Graham Anderson,
Peter Lane,
Mi-Yeon Kim
[show abstract]
[hide abstract]
ABSTRACT: Here, we identify cells within human adult secondary lymphoid tissues that are comparable in phenotype and location to the lymphoid tissue inducer (LTi) cells that persist in the adult mouse. Identified as CD117(+) CD3(-) CD56(-) cells, like murine LTi cells, they lack expression of many common lineage markers and express CD127, OX40L and TRANCE. These cells were detected at the interface between the B- and T- zones, as well as at the subcapsular sinus in LNs, the location where LTi cells reside in murine spleen and LNs. Furthermore, like murine LTi cells, these cells expressed high levels of IL-22 and upregulated IL-22 expression upon IL-23 stimulation. Importantly, these cells were not an NK cell subset since they showed no expression of IFN-γ and perforin. Interestingly, a subset of the CD117(+) CD3(-) CD56(-) OX40L(+) population expressed NKp46, again similar to recent findings in mice. Finally, these cells supported memory CD4(+) T-cell survival in an OX40L-dependent manner. Combined, these data indicate that the CD117(+) CD3(-) CD56(-) OX40L(+) cells in human secondary lymphoid tissues are comparable in phenotype, location and function to the LTi cells that persist within adult murine secondary lymphoid tissues.
European Journal of Immunology 03/2011; 41(6):1563-72. · 5.10 Impact Factor
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Saeeda Bobat,
Adriana Flores-Langarica,
Jessica Hitchcock,
Jennifer L Marshall,
Robert A Kingsley,
Margaret Goodall,
Cristina Gil-Cruz,
Karine Serre,
Denisse L Leyton,
Shirdi E Letran, Fabrina Gaspal,
Rebecca Chester,
Jayne L Chamberlain,
Gordon Dougan,
Constantino López-Macías,
Ian R Henderson,
James Alexander,
Ian C M MacLennan,
Adam F Cunningham
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ABSTRACT: Clearance of disseminated Salmonella infection requires bacterial-specific Th1 cells and IFN-γ production, and Th1-promoting vaccines are likely to help control these infections. Consequently, vaccine design has focused on developing Th1-polarizing adjuvants or Ag that naturally induce Th1 responses. In this study, we show that, in mice, immunization with soluble, recombinant FliC protein flagellin (sFliC) induces Th2 responses as evidenced by Ag-specific GATA-3, IL-4 mRNA, and protein induction in CD62L(lo) CD4(+) T cells without associated IFN-γ production. Despite these Th2 features, sFliC immunization can enhance the development of protective Th1 immunity during subsequent Salmonella infection in an Ab-independent, T-cell-dependent manner. Salmonella infection in sFliC-immunized mice resulted in augmented Th1 responses, with greater bacterial clearance and increased numbers of IFN-γ-producing CD4(+) T cells, despite the early induction of Th2 features to sFliC. The augmented Th1 immunity after sFliC immunization was regulated by T-bet although T-bet is dispensable for primary responses to sFliC. These findings show that there can be flexibility in T-cell responses to some subunit vaccines. These vaccines may induce Th2-type immunity during primary immunization yet promote Th1-dependent responses during later infection. This suggests that designing Th1-inducing subunit vaccines may not always be necessary since this can occur naturally during subsequent infection.
European Journal of Immunology 03/2011; 41(6):1606-18. · 5.10 Impact Factor
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ABSTRACT: While IL-4 directs CD4 T cells to produce Th2 cytokines (including IL-4, IL-13, IL-5) in vitro it has been shown that production of these cytokines can be induced in vivo in the absence of IL-4/IL-13/STAT-6 signaling. The present report shows that CD8 as well as CD4 T cells activated through their TCR, in vitro upregulate the Th2-features - IL-4, IL-13, IL-5, and GATA-3. However, in vivo while alum-precipitated antigen strongly and selectively induces these Th2-features in CD4 T cells, CD8 T cells mount a markedly different response to this antigen. This CD8 response is associated with strong proliferation and production of IFN-gamma, but no Th2-features are induced. Alum-protein formulations are widely used in human vaccines and typically induce strong antibody responses characterized by the differentiation of IL-4-producing CD4 T cells and immunoglobulin class switching to IgG1. Nevertheless, the mechanism responsible for CD4 Th2 and follicular helper T cell commitment triggered by these alum-protein vaccines is still poorly understood. Analysis of the in vivo response to alum-precipitated protein shows that while subsets of CD4 T cells strongly upregulate Th2 and follicular helper T cell features including the surface markers OX40, CXCR5, PD-1, IL-17RB and the transcription factor c-Maf, CD8 T cells do not. These discrete differences between responding CD4 and CD8 T cells provide further insight into the differences between Th2 polarization of CD4 T cells directed by IL-4 in vitro and the induction of IL-4 production by CD4 T cells in vivo in response to alum-precipitated protein.
Molecular Immunology 04/2010; 47(10):1914-22. · 2.90 Impact Factor
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ABSTRACT: Phylogeny indicates that in mammals memory CD4-dependent antibody responses evolved after monotremes split from the common ancestor of marsupial and eutherian mammals. This was strongly associated with the development of segregated B and T cell areas and the development of a linked lymph node network. The evolution of the lymphotoxin beta receptor in these higher mammals was key to the development of these new functions. Here, we argue that lymphoid tissue inducer cells played a pivotal role not only in the development of organized lymphoid structures but also in the subsequent genesis of the CD4-dependent class-switched memory antibody responses that depend on an organized infrastructure to work. In this review, we concentrate on the role of this cell type in the making of a tolerant CD4 T cell repertoire and in the sustenance of CD4 T cell responses for protective immunity.
Progress in molecular biology and translational science 01/2010; 92:159-74.
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ABSTRACT: The pathogenic outcomes of viral infection are often reminiscent of a dysfunctional immune system. Thus, cytomegalovirus (CMV) causes disruption of the lymphoid architecture and the functionality of lymphocytes, both of which are features of CD30 deficiency. It was therefore plausible that CD30 might interfere with CMV infection. The present study identifies CD30 as an inducible NK-cell receptor critical for innate immunity against CMV. Expression of CD30 integrates survival signals to NK cells that allow them to prevent viral spread and subsequent disintegration of secondary lymphoid tissue. Deficiency in CD30 results in exaggerated NK cell death and complete abrogation of the lymphoid architecture. Our data define the necessity of NK cells for protection of secondary lymphoid organs and describe a mechanism by which this protection is conferred.
European Journal of Immunology 10/2009; 39(10):2800-8. · 5.10 Impact Factor
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ABSTRACT: Although CD4(+) memory T cells reside within secondary lymphoid tissue, the major reservoir of these cells is in the lamina propria of the intestine. In this study, we demonstrate that, in the absence of signals through both OX40 and CD30, CD4(+) T cells are comprehensively depleted from the lamina propria. Deficiency in either CD30 or OX40 alone reduced CD4(+) T cell numbers, however, in mice deficient in both OX40 and CD30, CD4(+) T cell loss was greatly exacerbated. This loss of CD4(+) T cells was not due to a homing defect because CD30 x OX40-deficient OTII cells were not impaired in their ability to express CCR9 and alpha(4)beta(7) or traffic to the small intestine. There was also no difference in the priming of wild-type (WT) and CD30 x OX40-deficient OTII cells in the mesenteric lymph node after oral immunization. However, following oral immunization, CD30 x OX40-deficient OTII cells trafficked to the lamina propria but failed to persist compared with WT OTII cells. This was not due to reduced levels of Bcl-2 or Bcl-XL, because expression of these was comparable between WT and double knockout OTII cells. Collectively, these data demonstrate that signals through CD30 and OX40 are required for the survival of CD4(+) T cells within the small intestine lamina propria.
The Journal of Immunology 10/2009; 183(8):5079-84. · 5.79 Impact Factor
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ABSTRACT: Prior to acquiring a memory phenotype, antigen-activated CD8(+) T cells need to expand and then undergo a contraction phase. Utilizing two different antigenic stimuli, we provide evidence that the tumor necrosis factor receptors OX40 and CD30 integrate synergistic signals during the expansion phase to help maintain CD8(+) effectors. Thus, double deficiency in OX40 and CD30 leads to CD8(+) cell loss during expansion after immunization either with OVA or with murine CMV. Following their contraction, OX40- and CD30-deficient CD8(+) T cells persist normally in CMV-infected mice. In contrast, persistence after OVA challenge is dependent on OX40 and CD30. Collectively, our data define the important role of both OX40 and CD30 during CD8(+) T-cell activation, and show that long-term CD8 persistence after contraction is regulated not only by stimulatory receptors but also by the nature of the antigen or how the antigen is presented.
European Journal of Immunology 08/2009; 39(8):2120-5. · 5.10 Impact Factor
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ABSTRACT: Lymphoid tissue inducer cells express a diverse array of tumor necrosis family ligands, including those that bind CD30 and the lymphotoxin beta receptor. Both of these signaling pathways have been linked with B/T segregation in the spleen. In this study, we have dissected a lymphotoxin-independent CD30-dependent signal for the induction of expression of the T zone chemokine, CCL21. Reduced expression of CCL21 due to CD30 deficiency was functionally significant: mice deficient in both lymphotoxin and CD30 (dKO) signals had significantly smaller accumulations of lymphocytes in their splenic white pulp areas, with no evidence of focal aggregation of T cells. Furthermore, recruitment of wild-type CD4 T cells was poor in dKO mice compared with both wild-type or lymphotoxin-deficient mice. Phylogeny suggests that CD30 signals predated those through the lymphotoxin beta receptor. We suggest that CD30 signals from lymphoid tissue inducer cells were a primitive mechanism to recruit and prime CD4 T cells. This would have been a stepping stone in the evolution of the highly organized lymphotoxin dependent B and T white pulp areas within which CD4-dependent memory Ab responses now develop.
The Journal of Immunology 05/2009; 182(8):4771-5. · 5.79 Impact Factor
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ABSTRACT: Lymphoid tissue inducer (LTi) cells have a well established role in secondary lymphoid tissue development. Here, we report on the heterogeneity of LTi cells based on their CD4 and chemokine receptor expression. The CD4(-) LTi-cell population has a similar phenotype to the CD4(+) population, with similar chemokine-receptor-expressing subsets. In both embryonic and adult spleen the CD4(-) LTi-cell population is comparable as a proportion of total splenocytes to its CD4(+) counterpart. In contrast, different proportions of CD4(+) and CD4(-) LTi cells are found in different lymph nodes. Both CD4(+) and CD4(-) LTi cells share the anatomical location and are associated with vascular cell adhesion molecule-1-positive stromal cells in spleen and lymph nodes. The numbers of both CD4(+) and CD4(-) LTi cells in adult spleen are augmented in the presence of B cells. With the exception of CD4, there is a strong correlation coefficient (0.89) for gene expression between the two populations. Polymerase chain reaction analysis of individual CD4(+) and CD4(-) LTi cells shows that a similar proportion in embryonic and adult spleen co-expressed both CXCR5 and CCR7 or CXCR5 alone: 84.6% for adult CD4(+) and 87.6% for adult CD4(-); 95.3% for embryonic CD4(+) and 91.5% for embryonic CD4(-). Consistently fewer CCR7 single-positive cells were found in the CD4(+) and CD4(-) fractions in the embryo.
Immunology 07/2008; 124(2):166-74. · 3.32 Impact Factor
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Vasileios Bekiaris,
Olga Timoshenko,
Tie Zheng Hou,
Kai Toellner,
Saba Shakib, Fabrina Gaspal,
Fiona M McConnell,
Sonia M Parnell,
David Withers,
Chris D Buckley,
Clive Sweet,
Wayne M Yokoyama,
Graham Anderson,
Peter J L Lane
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ABSTRACT: In this study, we show that in the absence of a protective NK cell response, murine CMV causes destruction of splenic white and red pulp pulp areas in the first few days of infection. Destruction of T zone stroma is associated with almost complete loss of dendritic cells and T cells. We provide evidence that the virus replicates in red and white pulp stroma in vivo and in vitro. Control of white pulp viral replication is associated with migration of murine CMV-specific activated NK cells to white pulp areas, where they associate directly with podoplanin-expressing T zone stromal cells. Our data explain how NK cells protect the lymphoid-rich white pulp areas from CMV, allowing protective adaptive T cell-dependent immune responses to develop, and how this mechanism might break down in immunocompromised patients.
The Journal of Immunology 06/2008; 180(10):6768-76. · 5.79 Impact Factor
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ABSTRACT: Lymphoid tissue inducer cells (LTi) are known for their role in embryonic lymphoid tissue development. We have identified LTi in adult tissues including spleen and thymus, and provide evidence here for their presence in the submucosa of the intestine. From these observations it is clear that LTi play multiple roles in the adaptive immune system, notably the ability to recruit and sustain primed CD4 T cells in environments where they provide help to other cells. We speculate that their human equivalents could be potential targets for HIV infection and their destruction explains the pattern of loss of CD4 T cells.
Seminars in Immunology 05/2008; 20(3):159-63. · 6.39 Impact Factor
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ABSTRACT: CD30 and OX40 (CD134) are members of the TNFR superfamily expressed on activated CD4 T cells, and mice deficient in both these molecules harbor a striking defect in the capacity to mount CD4 T cell-dependent memory Ab responses. This article shows that these mice also fail to control Salmonella infection because both CD30 and OX40 signals are required for the survival but not commitment of CD4 Th1 cells. These signals are also needed for the survival of CD4 T cells activated in a lymphopenic environment. Finally, Salmonella and lymphopenia are shown to act synergistically in selectively depleting CD4 T cells deficient in OX40 and CD30. Collectively these findings identify a novel mechanism by which Th1 responses are sustained.
The Journal of Immunology 04/2008; 180(5):2824-9. · 5.79 Impact Factor
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ABSTRACT: CD4(+)CD3(-) lymphoid tissue inducer (LTi) cells are crucial for the development and organisation of lymph nodes and gut associated lymphoid tissues. In this report, we characterise their appearance in the developing spleen and highlight their importance in relation to the development of splenic T cell zones. LTi cells were detected in embryonic spleen from embryonic day 13, although their progenitors were present at embryonic day 12. These cells clustered initially around splenic blood vessels in a lymphotoxin (LT)-independent manner, but up-regulation of VCAM-1 expression on stromal cells associated with the blood vessels was LT dependent. After birth, T cell colonisation of these clusters to form nascent white pulp areas was also LT dependent. Transfer experiments reconstituting RAG(-/-) mice with either WT or LTalpha(-/-) splenocytes demonstrated that lymphocyte expression of LT was not essential for the organisation of a discrete CD3(+) T cell zone with localised podoplanin and CCL21 expression. Our studies indicate that a combination of LT signals from LTi cells and LT-independent signals from lymphocytes is sufficient for expression of podoplanin and CCL21 on splenic T cell zone stroma and subsequent T cell organisation.
European Journal of Immunology 12/2007; 37(11):3240-3245. · 5.10 Impact Factor
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Adam F Cunningham, Fabrina Gaspal,
Karine Serre,
Elodie Mohr,
Ian R Henderson,
Anthony Scott-Tucker,
Sinead M Kenny,
Mahmood Khan,
Kai-Michael Toellner,
Peter J L Lane,
Ian C M MacLennan
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ABSTRACT: T-dependent Ab responses are characterized by parallel extrafollicular plasmablast growth and germinal center (GC) formation. This study identifies that, in mice, the Ab response against Salmonella is novel in its kinetics and its regulation. It demonstrates that viable, attenuated Salmonella induce a massive early T-dependent extrafollicular response, whereas GC formation is delayed until 1 mo after infection. The extrafollicular Ab response with switching to IgG2c, the IgG2a equivalent in C57BL/6 mice, is well established by day 3 and persists through 5 wk. Switching is strongly T dependent, and the outer membrane proteins are shown to be major targets of the early switched IgG2c response, whereas flagellin and LPS are not. GC responses are associated with affinity maturation of IgG2c, and their induction is associated with bacterial burden because GC could be induced earlier by treating with antibiotics. Clearance of these bacteria is not a consequence of high-affinity Ab production, for clearance occurs equally in CD154-deficient mice, which do not develop GC, and wild-type mice. Nevertheless, transferred low- and high-affinity IgG2c and less efficiently IgM were shown to impede Salmonella colonization of splenic macrophages. Furthermore, Ab induced during the infection markedly reduces bacteremia. Thus, although Ab does not prevent the progress of established splenic infection, it can prevent primary infection and impedes secondary hemogenous spread of the disease. These results may explain why attenuated Salmonella-induced B cell responses are protective in secondary, but not primary infections.
The Journal of Immunology 06/2007; 178(10):6200-7. · 5.79 Impact Factor
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ABSTRACT: During B cell development, proliferative expansion takes place after expression of the pre-BCR. At this pre-BII cell stage, the IL-7Ralpha is also expressed. Some in vitro studies suggest that pre-BCR-dependent expansion relies on the IL-7Ralpha, and others that it does not. It has also been suggested that the pre-BCR mediates down-regulation of the IL-7Ralpha. However, the in vivo relationship between the pre-BCR and the IL-7Ralpha has not been previously examined. Here, we have investigated this by establishing mice lacking both receptors. Our results show that in the absence of the IL-7Ralpha, the pre-BII population is reduced, as previously seen in mice lacking the pre-BCR, demonstrating that the IL-7Ralpha is important at this stage. A deficiency in both receptors results in a further reduction of the pre-BII cell population. We conclude that both the IL-7Ralpha and the pre-BCR are required for optimal pre-BII cell expansion. Furthermore, IL-7Ralpha expression levels are normal in pre-BCR-deficient mice, suggesting that the pre-BCR does not mediate its down-regulation. As a consequence of the absence of both receptors, the peripheral B cell pool is severely depleted, resulting in atypical splenic B cell structures and reduced serum Ig levels.
European Journal of Immunology 07/2005; 35(6):1969-76. · 5.10 Impact Factor
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ABSTRACT: During B cell development, proliferative expansion takes place after expression of the pre-BCR. At this pre-BII cell stage, the IL-7Rα is also expressed. Some in vitro studies suggest that pre-BCR-dependent expansion relies on the IL-7Rα, and others that it does not. It has also been suggested that the pre-BCR mediates down-regulation of the IL-7Rα. However, the in vivo relationship between the pre-BCR and the IL-7Rα has not been previously examined. Here, we have investigated this by establishing mice lacking both receptors. Our results show that in the absence of the IL-7Rα, the pre-BII population is reduced, as previously seen in mice lacking the pre-BCR, demonstrating that the IL-7Rα is important at this stage. A deficiency in both receptors results in a further reduction of the pre-BII cell population. We conclude that both the IL-7Rα and the pre-BCR are required for optimal pre-BII cell expansion. Furthermore, IL-7Rα expression levels are normal in pre-BCR-deficient mice, suggesting that the pre-BCR does not mediate its down-regulation. As a consequence of the absence of both receptors, the peripheral B cell pool is severely depleted, resulting in atypical splenic B cell structures and reduced serum Ig levels.
European Journal of Immunology 05/2005; 35(6):1969 - 1976. · 5.10 Impact Factor
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ABSTRACT: The cytokine IL-7 and its receptor are essential for normal B and T lymphopoiesis. We have analyzed the role of this receptor in B cell development throughout ontogeny in IL-7 receptor alpha-deficient mice. We demonstrate that the IL-7 receptor becomes progressively more important with age. B lymphopoiesis takes place, albeit at reduced levels, in fetal liver and bone marrow of young mice, but is arrested in adults. The outcome is a severe reduction, from an early age, in peripheral B cells including follicular, marginal zone and B-1 B cells as well as perturbed splenic B cell structures, which are restored after adoptive transfer of normal spleen cells. We conclude that in the absence of the IL-7 receptor, the residual B lymphopoiesis occurring early in ontogeny must be facilitated by another component, whereas the IL-7 receptor is the key factor in adults. The impairment of marginal zone and B-1 B cells in IL-7 receptor- but not IL-7-deficient mice suggests non-redundant functions for the IL-7 receptor ligands, IL-7 and thymic stromal lymphopoietin.
European Journal of Immunology 01/2005; 34(12):3595-603. · 5.10 Impact Factor
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ABSTRACT: Phylogeny indicates that in mammals memory CD4-dependent antibody responses evolved after monotremes split from the common ancestor of marsupial and eutherian mammals. This was strongly associated with the development of segregated B and T cell areas and the development of a linked lymph node network. The evolution of the lymphotoxin beta receptor in these higher mammals was key to the development of these new functions. Here, we argue that lymphoid tissue inducer cells played a pivotal role not only in the development of organized lymphoid structures but also in the subsequent genesis of the CD4-dependent class-switched memory antibody responses that depend on an organized infrastructure to work. In this review, we concentrate on the role of this cell type in the making of a tolerant CD4 T cell repertoire and in the sustenance of CD4 T cell responses for protective immunity.
Progress in Molecular Biology and Translational Science.
