Viral Superantigen Drives Extrafollicular and Follicular B Cell Differentiation Leading to Virus-specific Antibody Production

Luther, Sanjiv A.; Gulbranson-Judge, Adam; Acha‐Orbea, Hans; MacLennan, Ian C. M.

doi:10.1084/jem.185.3.551

Cited by 92 publications

(126 citation statements)

References 58 publications

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“…1A, B, day 0). In the draining LN the frequency and number of Vb6 + cells rose sharply from day 3 after injection of superantigen, as previously described [1]. Between day 7 and 10, Vb6 + CD4 T cell numbers in the draining LN fell dramatically.…”

Section: Resultssupporting

confidence: 82%

“…Immunohistology was performed as described previously [1,15,16]. An additional antibody used was rabbit anti-mouse Ki-67 antiserum (gift from Johannes Gerdes, Borstel, Germany) labeled with swine anti-rabbit Ig antiserum (Dako, Glostrup, Denmark), followed by rabbit PAP (Dako).…”

Section: Immunohistologymentioning

confidence: 99%

“…Naive CD4 T cells enter cell cycle after being primed by cognate interaction with dendritic cells in the T zones. This results in a strong expansion of antigen-specific lymphocytes within the LN [1]. The high number of antigen-responding CD4 T cells typically is not sustained, and only a small proportion of the cells persists [2,3].…”

Section: Introductionmentioning

confidence: 99%

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Recirculating CD4 memory T cells mount rapid secondary responses without major contributions from follicular CD4 effectors and B cells

et al. 2007

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For weeks after primary immunization with thymus-dependent antigens the responding lymph nodes contain effector CD4 T cells in T zones and germinal centers as well as recirculating memory T cells. Conversely, remote nodes, not exposed to antigen, only receive recirculating memory cells. We assessed whether lymph nodes with follicular effector CD4 T cells in addition to recirculating memory CD4 T cells mount a more rapid secondary response than nodes that only contain recirculating memory cells. Also, the extent to which T cell frequency governs accelerated CD4 T cell recall responses was tested. For this, secondary antibody responses to a superantigen, where the frequency of responding T cells is not increased at the time of challenge, were compared with those to conventional protein antigens. With both types of antigens similar accelerated responses were elicited in the node draining the site of primary immunization and in the contralateral node, not previously exposed to antigen. Thus recirculating memory cells are fully capable of mounting accelerated secondary responses, without the assistance of CD4 effector T cells, and accelerated memory responses are not solely dependent on higher T cell frequencies. Accelerated memory CD4 T cell responses were also seen in B cell-deficient mice. IntroductionPrimary immunization with thymus-dependent antigens results in specific T and B cell responses in draining lymph nodes (LN). Naive CD4 T cells enter cell cycle after being primed by cognate interaction with dendritic cells in the T zones. This results in a strong expansion of antigen-specific lymphocytes within the LN [1]. The high number of antigen-responding CD4 T cells typically is not sustained, and only a small proportion of the cells persists [2,3]. Nevertheless, CD4 memory T cells can survive for long periods without continued contact with antigen [4][5][6], although it has been reported that such antigen-deprived cells may lack competence on reactivation in vivo [7].Antigen-experienced CD4 T cells have been classified into central memory and effector memory cells [8]. Central memory T cells have a slow turnover and express high levels of CCR7 and CD62L, which are both associated with homing to T zones of lymphoid tissues. Conversely, effector memory T cells home to inflamed tissues, have a rapid turnover, and are CCR7 -CD62L low . Both effector and central memory populations in vitro respond rapidly to low doses of antigen, but while LN draining the site of immunization develop substantial populations of antigen-specific CD4 effector T cells located in the follicles and outer T zone; these are not found in the remote LN. After immunization with limiting amounts of antigen, most antigen is trapped in the LN draining the site of immunization (draining LN) and lymphocyte activation is limited to this site. Several weeks after immunization draining LN will contain effector and memory CD4 T cells. In contrast, LN remote from the site of primary immunization (remote LN) will only have received recirculating memory ...

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Section: Resultssupporting

confidence: 82%

Section: Immunohistologymentioning

confidence: 99%

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Recirculating CD4 memory T cells mount rapid secondary responses without major contributions from follicular CD4 effectors and B cells

et al. 2007

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“…The different B cell populations were isolated as follows using FACS sortring (Table 1 and [28]. This syndecan-1 int population made up about one third to one tenth of the syndecan-1-expressing B cells (see Fig.…”

Section: Isolation Of the Differentiating B Cell Subsets During Lymphmentioning

confidence: 99%

Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes

et al. 2001

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During T cell-dependent antibody responses lymph node B cells differentiate either to plasmablasts that grow in the medullary cords, or to blasts that proliferate in follicles forming germinal centers. Many plasmablasts differentiate to plasma cells locally, but some leave the medullary cords and migrate to downstream lymph nodes. To assess the basis for this migration, changes in the responsiveness of B cells to a range of chemokines have been studied as they differentiate. Naive B cells express high levels of CCR6, CCR7, CXCR4 and CXCR5. When activated B cells grow in follicles the expression of these chemokine receptors and the responsiveness to the respective chemokines is retained. During the extrafollicular response, plasmablast expression of CXCR5 and responsiveness to B-lymphocyte chemoattractant (CXCR5) as well as to secondary lymphoid tissue chemokine (CCR7) and stromal cell-derived factor (SDF)-1 (CXCR4) are lost while a weak response towards the CCR6 chemokine LARC is maintained. Despite losing responsiveness to SDF-1, extrafollicular plasmablasts still express high levels of CXCR4 on the cell surface. These results suggest that the combined loss of chemokine receptor expression and of chemokine responsiveness may be a necessary prerequisite for cells to migrate to the medullary cords and subsequently enter the efferent lymph.

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“…The SAg response is comparable to classical T cell-B cell interactions and leads to both follicular and extrafollicular B cell responses in the lymph nodes (LN) draining the site of injection. In the draining LN an ongoing germinal center (GC) reaction is observed, which is maintained for Ͼ120 days (4). MMTV has a small genome and a simple genome organization.…”

mentioning

confidence: 99%

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

Finke

Luther²,

Acha‐Orbea³

2002

Proc. Natl. Acad. Sci. U.S.A.

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Mouse mammary tumor virus (MMTV) infection establishes chronic germinal centers and a lifelong neutralizing Ab response. We show that removal of the draining lymph node after establishment of the germinal center reaction led to complete loss of neutralizing Abs despite comparable infection levels in peripheral lymphocytes. Importantly, in the absence of neutralization, only the exocrine organs mammary gland, salivary gland, pancreas, and skin showed strikingly increased infection, resulting in accelerated mammary tumor development. Induction of stronger neutralization did not influence chronic infection levels of peripheral lymphoid organs but strongly inhibited mammary gland infection and virus transmission to the next generation. Taken together, we provide evidence that a tight equilibrium in virus neutralization allows limited infection of exocrine organs and controls cancer development in susceptible mouse strains. These experiments show that a strong neutralizing Ab response induced after infection is not able to control lymphoid MMTV infection. Strong neutralization, however, is capable of blocking amplification of mammary gland infection, tumor development, and virus transmission to the next generation. The results also indicate a role of neutralization in natural resistance to MMTV infection.

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Viral Superantigen Drives Extrafollicular and Follicular B Cell Differentiation Leading to Virus-specific Antibody Production

Cited by 92 publications

References 58 publications

Recirculating CD4 memory T cells mount rapid secondary responses without major contributions from follicular CD4 effectors and B cells

Recirculating CD4 memory T cells mount rapid secondary responses without major contributions from follicular CD4 effectors and B cells

Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

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