An Early CD4+ T Cell–dependent Immunoglobulin A Response to Influenza Infection in the Absence of Key Cognate T–B Interactions

Sangster, Mark Y.; Riberdy, Janice M.; Gonzalez, Maricela; Topham, David J.; Baumgarth, Nicole; Doherty, Peter C.

doi:10.1084/jem.20021745

Cited by 105 publications

(101 citation statements)

References 52 publications

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“…5C) indicating a trapping of B cells and ␥␦ T cells (but not ␣␤ T cells) in regional lymph nodes and thus the potential for local ␥␦ T cell-B cell interaction during early influenza virus infection. Although detailed information on ␥␦ T cell or NK T cell-mediated B cell help during influenza virus infection is lacking, the importance of noncognate help for the induction of early local virus-specific IgA responses to influenza virus infection in the MLN has been demonstrated (47). Moreover, the presence of neutralizing IgG Abs and B cell memory formation following infection of TCR ␣␤ gene-targeted mice with vesicular stomatitis virus was shown to dependent on ␥␦ T cells (48).…”

Section: Discussionmentioning

confidence: 99%

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

Chang¹,

Coro²,

Rau³

et al. 2007

The Journal of Immunology

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Induction of primary B cell responses requires the presence of Ag and costimulatory signals by T cells. Innate signals further enhance B cell activation. The precise nature and kinetics of such innate immune signals and their functional effects are unknown. This study demonstrates that influenza virus-induced type I IFN is the main innate stimulus affecting local B cells within 48 h of infection. It alters the transcriptional profile of B cells and selectively traps them in the regional lymph nodes, presumably via up-regulation of CD69. Somewhat paradoxically, innate B cell stimulation inhibited the ability of regional lymph node B cells to clonally expand following BCR-mediated stimulation. This inhibition was due to IFNR-signaling independent B cell intrinsic, as well as IFNR-dependent B cell extrinsic, regulation induced following influenza infection. IFNR-mediated signals also reduced B cell migration to various chemotactic agents. Consistent with the lack of responsiveness to CCR7 ligands, unaltered or reduced expression of MHC class II and genes associated with MHC class II Ag processing/presentation and CD40, B cells were unable to induce proliferation of naive CD4 T cells. Instead, they showed increased expression of a subset of nonclassical MHC molecules that facilitate interaction with γδ T cells and NK T cells. We conclude that type I IFN is the main “third” B cell signal following influenza infection causing early trapping of B cells in regional lymph nodes and, at a time when cognate T cell help is rare, enhancing their propensity to interact with innate immune cells for noncognate stimulation.

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Section: Discussionmentioning

confidence: 99%

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

Chang¹,

Coro²,

Rau³

et al. 2007

The Journal of Immunology

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“…In a primary influenza infection, virus-specific T-and B-cell responses are difficult to detect until 5 days after viral inoculation (39,46). Assuming that the contributions of the adaptive antibody and cellular responses of the immune system are negligible during this period, we used model 2 to fit the viral titer data during the first 5 days of infection.…”

Section: Resultsmentioning

confidence: 99%

Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

Miao

Hollenbaugh

Zand

et al. 2010

J Virol

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350

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Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is ϳ1.2 days, and the half-life of free infectious IAV is ϳ4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is ϳ0.5 days, and the average half-life of free infectious virus is ϳ1.8 min. During the adaptive phase, model fitting confirms that CD8 ؉ CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity.

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“…Protective immunity against a primary infection with lethal type A influenza virus is to a large degree mediated by the humoral response, as shown by studies in which mice lacking B cells rapidly succumb to influenza infection despite the ability to mount a vigorous CD8 ϩ T cell response (1,2). Class switch recombination to Ab isotypes other than IgM is largely dependent upon T cell help, although Abs of the IgG isotypes are detectable at reduced titers in the absence of T-B interaction (3)(4)(5). Detailed analysis of the efficacy of Ab isotypes showed that IgG isotypes are primarily responsible for neutralizing influenza virus during primary and challenge infections (6,7), and earlier studies identified IgG2a as a key isotype for Ab-mediated effector functions in C57BL/6 mice (8 -10).…”

mentioning

confidence: 96%

TLR Signaling Fine-Tunes Anti-Influenza B Cell Responses without Regulating Effector T Cell Responses

Heer

Shamshiev

Donda³

et al. 2007

The Journal of Immunology

187

195

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Influenza is a ssRNA virus that has been responsible for widespread morbidity and mortality; however, the innate immunological mechanisms that drive the adaptive anti-influenza immune response in vivo are yet to be fully elucidated. TLRs are pattern recognition receptors that bind evolutionarily conserved pathogen-associated molecular patterns, induce dendritic cell maturation, and consequently aid the development of effective immune responses. We have examined the role of TLRs in driving effective T and B cell responses against influenza virus. We found TLR3 and its associated adapter molecule, Toll/IL-R domain-containing adaptor-inducing IFN-β, did not play a role in the development of CD4+ or CD8+ T cell responses against influenza virus, nor did they influence influenza-specific B cell responses. Surprisingly, TLR7 and MyD88 also played negligible roles in T cell activation and effector function upon infection with influenza virus; however, their signaling was critical for regulating anti-influenza B cell Ab isotype switching. The induction of appropriate anti-influenza humoral responses involved stimulation of TLRs on B cells directly and TLR-induced production of IFN-α, which acted to reduce IgG1 and increase IgG2a/c class switching. Notably, direct TLR signaling on B cells or T cell help through the CD40-CD40L interaction was sufficient to support B cell proliferation and IgG1 production, whereas IFN-α was critical for fine-tuning the nature of the isotype switch. Taken together, these data reveal that TLR signaling is not required for anti-influenza T cell responses, but through both direct and indirect means orchestrates appropriate anti-influenza B cell responses.

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An Early CD4+ T Cell–dependent Immunoglobulin A Response to Influenza Infection in the Absence of Key Cognate T–B Interactions

Cited by 105 publications

References 52 publications

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

TLR Signaling Fine-Tunes Anti-Influenza B Cell Responses without Regulating Effector T Cell Responses

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