Gammaherpesvirus-infected germinal center cells express a distinct immunoglobulin repertoire

Zelazowska, Monika A.; Dong, Qiwen; Plummer, Joshua B.; Zhong, Yi; Liu, Bin; Krug, Laurie T.; McBride, Kevin M.

doi:10.26508/lsa.201900526

Cited by 8 publications

(28 citation statements)

References 77 publications

(92 reference statements)

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“…This suggests that KSHV might edit the BCR in the peripheral lymphoid tissues and lead to some potential autoreactive or non-functional B cells outside of the bone marrow. As detailed and discussed below, Igκ light chain bias was also recently reported by us [ 88 ] and Collins et al [ 89 ] for MHV68-infected B cells from mice at the peak of latency in the spleen. It is unclear by what mechanism KSHV drives receptor editing and for what purpose this might serve the virus in the host.…”

Section: Germinal Center Processes That Shape B Cell Evolution Andsupporting

confidence: 72%

“…Two recent studies used a traceable MHV68 infection mouse model to analyze the Ig repertoire of infected cells [ 88 , 89 ]. A transgenic virus which expresses histone H2B fused to EYFP fluorescent protein (MHV68-H2BYFP) [ 158 ] was used to infect mice and isolate MHV68+ B cells.…”

Section: Immunoglobulin Bias In Gammaherpesvirus Infectionmentioning

confidence: 99%

“…Significantly, in the MHV68+ population, Ighv10-1 was highly utilized (~20% of all MHV68+ B cells), with little representation of Ighv1-82 in the MHV68+ population. The bias for Ighv10-1 was not only observed recurrently within individual mice, but also spanned three individual mouse facilities [ 88 , 89 ]. Furthermore, Collins et al [ 89 ] examined MHV68+ plasma cells, observing the biased Ig repertoire and prominent Ighv10-1 utilization.…”

Section: Immunoglobulin Bias In Gammaherpesvirus Infectionmentioning

confidence: 99%

“…Zelazowska et al [ 88 ] examined clonal expansion and overlap in detail, finding very different dynamics between the MHV68+ and MHV68- populations of individual mice. MHV68+ cells were much more confined in the use of IGHV genes.…”

Section: Immunoglobulin Bias In Gammaherpesvirus Infectionmentioning

confidence: 99%

“…The SHM in MHV68+ cells did not display a physiologically relevant difference between MHV68+ and MHV68- populations [ 88 , 89 ]. Mutation location was significantly biased towards the antigen-binding CDR loops, an indication of antigen selection, since mutations are randomly generated, but clones with improved affinity were antigen selected [ 88 ]. Furthermore, the CDR3 length and charge characteristics as well as isotype switching were all similar between the MHV68+ and MHV68- populations.…”

Section: Immunoglobulin Bias In Gammaherpesvirus Infectionmentioning

confidence: 99%

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Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

Zelazowska

McBride

Krug

2020

Viruses

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A common biologic property of the gammaherpesviruses Epstein–Barr Virus and Kaposi sarcoma herpesvirus is their use of B lymphocytes as a reservoir of latency in healthy individuals that can undergo oncogenic transformation later in life. Gammaherpesviruses (GHVs) employ an impressive arsenal of proteins and non-coding RNAs to reprogram lymphocytes for proliferative expansion. Within lymphoid tissues, the germinal center (GC) reaction is a hub of B cell proliferation and death. The goal of a GC is to generate and then select for a pool of immunoglobulin (Ig) genes that will provide a protective humoral adaptive immune response. B cells infected with GHVs are detected in GCs and bear the hallmark signatures of the mutagenic processes of somatic hypermutation and isotype class switching of the Ig genes. However, data also supports extrafollicular B cells as a reservoir engaged by GHVs. Next-generation sequencing technologies provide unprecedented detail of the Ig sequence that informs the natural history of infection at the single cell level. Here, we review recent reports from human and murine GHV systems that identify striking differences in the immunoglobulin repertoire of infected B cells compared to their uninfected counterparts. Implications for virus biology, GHV-associated cancers, and host immune dysfunction will be discussed.

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Section: Germinal Center Processes That Shape B Cell Evolution Andsupporting

confidence: 72%

Section: Immunoglobulin Bias In Gammaherpesvirus Infectionmentioning

confidence: 99%

Section: Immunoglobulin Bias In Gammaherpesvirus Infectionmentioning

confidence: 99%

Section: Immunoglobulin Bias In Gammaherpesvirus Infectionmentioning

confidence: 99%

Section: Immunoglobulin Bias In Gammaherpesvirus Infectionmentioning

confidence: 99%

See 3 more Smart Citations

Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

Zelazowska

McBride

Krug

2020

Viruses

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Kidins220 regulates the development of B cells bearing the λ light chain

Schaffer

Fiala

Hils

et al. 2022

Preprint

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The ratio between Igκ and Igλ light chain (LC)-expressing B cells varies considerably between species. We recently identified Kinase D-interacting substrate of 220 kDa (Kidins220) as an interaction partner of the BCR. In vivo ablation of Kidins220 in B cells resulted in a marked reduction of λLC-expressing B cells. Kidins220 knockout B cells fail to open and recombine the genes of the λLC locus, even in genetic scenarios where the κLC genes cannot be rearranged or where the κLC confers autoreactivity. κLC gene recombination and expression in Kidins220-deficient B cells is normal. Kidins220 regulates the development of λLC B cells by enhancing the survival of developing B cells and thereby extending the time-window in which the λLC locus opens and the genes are rearranged and transcribed. Further, our data suggest that Kidins220 guarantees optimal pre-BCR and BCR signaling to induce λLC locus opening and gene recombination during B cell development and receptor editing.One Sentence SummaryWe demonstrate that the scaffold protein Kidins220 regulates the development of λLC B cells by supporting B cell precursor survival and optimizing pre-BCR and BCR signaling to open, recombine, and transcribe the genes of the λLC locus.

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B cell-intrinsic STAT3-mediated support of latency and interferon suppression during murine gammaherpesvirus 68 infection revealed through anin vivocompetition model

Hogan

Owens

Reynoso

et al. 2023

Preprint

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Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor STAT3. To better understand the role of STAT3 during gammaherpesvirus latency and immune control, we utilized murine gammaherpesvirus 68 (MHV68) infection. Genetic deletion of STAT3 in B cells of CD19cre/+Stat3f/f mice reduced peak latency approximately 7-fold. However, infected CD19cre/+Stat3f/f mice exhibited disordered germinal centers and heightened virus-specific CD8 T cell responses compared to WT littermates. To circumvent the systemic immune alterations observed in the B cell-STAT3 knockout mice and more directly evaluate intrinsic roles for STAT3, we generated mixed bone marrow chimeras consisting of WT and STAT3-knockout B cells. Using a competitive model of infection, we discovered a dramatic reduction in latency in STAT3-knockout B cells compared to their WT B cell counterparts in the same lymphoid organ. RNA sequencing of sorted germinal center B cells revealed that STAT3 promotes proliferation and B cell processes of the germinal center but does not directly regulate viral gene expression. Last, this analysis uncovered a STAT3-dependent role for dampening type I IFN responses in newly infected B cells. Together, our data provide mechanistic insight into the role of STAT3 as a latency determinant in B cells for oncogenic gammaherpesviruses.

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Gammaherpesvirus-infected germinal center cells express a distinct immunoglobulin repertoire

Cited by 8 publications

References 77 publications

Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

Kidins220 regulates the development of B cells bearing the λ light chain

B cell-intrinsic STAT3-mediated support of latency and interferon suppression during murine gammaherpesvirus 68 infection revealed through anin vivocompetition model

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