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Memory B cells form in aged mice despite impaired affinity maturation and germinal center kinetics

Goenka, Radhika ; Scholz, Jean L. ; Naradikian, Martin S. ; [et al.]

Elsevier BV ; 2014

In: Experimental Gerontology Vol. 54 ( 2014-06), p. 109-115

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In: Experimental Gerontology, Elsevier BV, Vol. 54 ( 2014-06), p. 109-115

Type of Medium: Online Resource

ISSN: 0531-5565

URL: Article

DOI: 10.1016/j.exger.2013.12.013

Language: English

Publisher: Elsevier BV

Publication Date: 2014

detail.hit.zdb_id: 2005397-6

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T Regulatory Cells Support Plasma Cell Populations in the Bone Marrow

Glatman Zaretsky, Arielle ; Konradt, Christoph ; Dépis, Fabien ; [et al.]

Elsevier BV ; 2017

In: Cell Reports Vol. 18, No. 8 ( 2017-02), p. 1906-1916

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In: Cell Reports, Elsevier BV, Vol. 18, No. 8 ( 2017-02), p. 1906-1916

Type of Medium: Online Resource

ISSN: 2211-1247

URL: Article

DOI: 10.1016/j.celrep.2017.01.067

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 2649101-1

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B Lymphocytes Provide an Infection Niche for Intracellular Bacterium Brucella abortus

Goenka, Radhika ; Guirnalda, Patrick D. ; Black, Samuel J. ; [et al.]

Oxford University Press (OUP) ; 2012

In: The Journal of Infectious Diseases Vol. 206, No. 1 ( 2012-7-1), p. 91-98

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In: The Journal of Infectious Diseases, Oxford University Press (OUP), Vol. 206, No. 1 ( 2012-7-1), p. 91-98

Type of Medium: Online Resource

ISSN: 1537-6613 , 0022-1899

URL: Article

DOI: 10.1093/infdis/jis310

RVK:

XA 10000

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2012

detail.hit.zdb_id: 1473843-0

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Positive selection during affinity maturation relies on T cell derived BLyS (61.3)

Goenka, Radhika ; Mathews, Andrew ; O'Neill, Patrick ; [et al.]

The American Association of Immunologists ; 2011

In: The Journal of Immunology Vol. 186, No. 1_Supplement ( 2011-04-01), p. 61.3-61.3

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 1_Supplement ( 2011-04-01), p. 61.3-61.3

Abstract: Protective humoral immunity relies on high affinity B cell clones that are generated and selected during the germinal center (GC) reaction. To determine whether BLyS family member(s) play a role in this process, we assessed their distribution within the GC. We show that majority of the GC is devoid of BLyS despite the presence of ample BLyS in the adjacent follicular regions. The paucity of BLyS correlates with down-regulation of TACI receptor on GC B cells and likewise follicular B cells in TACI-deficient mice bind less BLyS. TACI down-regulation on follicular B cells is mediated by IL-21 in a surrogate thymus-dependent stimulation. Furthermore, some BLyS staining is detectable in the light zone associated by T Follicular Helper cells (TFH). The expression of BLyS by TFH is crucial for appropriate GC evolution, since efficient affinity maturation fails in mixed bone marrow chimeras where T cells are deficient in BLyS. We conclude that positive selection during affinity maturation relies on restricted sources of BLyS on GC TFH that provide survival signals to preserve high affinity clones.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.186.Supp.61.3

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2011

detail.hit.zdb_id: 1475085-5

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Chronic Spinal Cord Injury Impairs Primary Antibody Responses but Spares Existing Humoral Immunity in Mice

Oropallo, Michael A. ; Held, Katherine S. ; Goenka, Radhika ; [et al.]

The American Association of Immunologists ; 2012

In: The Journal of Immunology Vol. 188, No. 11 ( 2012-06-01), p. 5257-5266

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 188, No. 11 ( 2012-06-01), p. 5257-5266

Abstract: Spinal cord injury (SCI) results in immune depression. To better understand how injury inhibits humoral immunity, the effects of chronic thoracic SCI on B cell development and immune responses to thymus-independent type 2 and thymus-dependent Ags were determined. Mice received complete crush injury or control laminectomy at either thoracic level 3, which disrupts descending autonomic control of the spleen, or at thoracic level 9, which conserves most splenic sympathetic activity. Although mature B cell numbers were only mildly reduced, bone marrow B cell production was transiently but profoundly depressed immediately after injury. Despite the return of normal B cell production 4 wk after SCI, mice receiving thoracic level 3 injury showed a significant reduction in their ability to mount primary thymus-independent type 2 or thymus-dependent immune responses. The latter were marked by decreases in germinal center B cells as well as class-switched high-affinity Ab-secreting cells. Importantly, injury did not affect affinity maturation per se, pre-existing B cell memory, or secondary humoral immune responses. Taken together, these findings show that chronic high thoracic SCI impairs the ability to mount optimal Ab responses to new antigenic challenges, but spares previously established humoral immunity.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.1101934

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2012

detail.hit.zdb_id: 1475085-5

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T follicular helper cells require cognate B cell interactions for acquisition of full effector function (63.4)

Barnett, Lisa ; Goenka, Radhika ; Silver, Jonathan ; [et al.]

The American Association of Immunologists ; 2011

In: The Journal of Immunology Vol. 186, No. 1_Supplement ( 2011-04-01), p. 63.4-63.4

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 1_Supplement ( 2011-04-01), p. 63.4-63.4

Abstract: Follicular helper T cells (TFH) are a unique subset of CD4+ helper T cells that are critical effectors of thymus-dependent humoral immune responses, yet much about their development in vivo remains unclear and controversial. The requirements for different antigen presenting cell subsets in TFH formation are not yet fully understood. By transiently ablating or restricting MHCII antigen presentation to CD11chi dendritic cells (DCs), we show that cognate, MHCII dependent interactions with DCs are both necessary and sufficient for the formation of CXCR5+, ICOS+ TFH cells that express the key transcription factor Bcl6, which governs their differentiation. However, TFH cells that do not undergo TCR-MHCII-dependent interactions with B cells lack a small subset of GL-7+ PD1hi cells found in the germinal center (GC) and GCs fail to form. These TFH exhibit a significant reduction in their ability to produce IL-21 when compared to TFH cells generated in the presence of cognate B cell interactions. Consistent with these data, in vitro priming of naïve T cells by B cells, but not DCs, induces optimal IL-21 production, which, in turn, induces a GC B cell transcriptional profile. Thus, this study supports a multi-step model for priming effector TFH in which DCs activate CD4+ T cell towards a poised intermediate which can then interact with responding B cells to sustain the GC status of both cell types.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.186.Supp.63.4

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2011

detail.hit.zdb_id: 1475085-5

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CTLA4-Ig–Based Bifunctional Costimulation Inhibitor Blocks CD28 and ICOS Signaling to Prevent T Cell Priming and Effector Function

Goenka, Radhika ; Xu, Zhenghai ; Samayoa, Josue ; [et al.]

The American Association of Immunologists ; 2021

In: The Journal of Immunology Vol. 206, No. 5 ( 2021-03-01), p. 1102-1113

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 206, No. 5 ( 2021-03-01), p. 1102-1113

Abstract: CTLA4-Ig/abatacept dampens activation of naive T cells by blocking costimulation via CD28. It is an approved drug for rheumatoid arthritis but failed to deliver efficacy in a number of other autoimmune diseases. One explanation is that activated T cells rely less on CD28 signaling and use alternate coreceptors for effector function. ICOS is critical for activation of T-dependent humoral immune responses, which drives pathophysiology of IgG-mediated autoimmune diseases. In this study, we asked whether CD28 and ICOS play nonredundant roles for maintenance of T-dependent responses in mouse models. Using a hapten–protein immunization model, we show that during an ongoing germinal center response, combination treatment with CTLA4-Ig and ICOS ligand (ICOSL) blocking Ab completely dissolves ongoing germinal center responses, whereas single agents show only partial activity. Next, we took two approaches to engineer a therapeutic molecule that blocks both pathways. First, we engineered CTLA4-Ig to enhance binding to ICOSL while retaining affinity to CD80/CD86. Using a library approach, binding affinity of CTLA4-Ig to human ICOSL was increased significantly from undetectable to 15–42 nM; however, the affinity was still insufficient to completely block binding of ICOSL to ICOS. Second, we designed a bispecific costimulation inhibitor with high-affinity CTLA4 extracellular domains fused to anti-ICOSL Ab termed bifunctional costimulation inhibitor. With this bispecific approach, we achieved complete inhibition of CD80 and CD86 binding to CD28 as well as ICOS binding to ICOSL. Such bispecific molecules may provide greater therapeutic benefit in IgG-mediated inflammatory diseases compared with CTLA4-Ig alone.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.2001100

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2021

detail.hit.zdb_id: 1475085-5

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Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation

Goenka, Radhika ; Matthews, Andrew H. ; Zhang, Bochao ; [et al.]

Rockefeller University Press ; 2014

In: Journal of Experimental Medicine Vol. 211, No. 1 ( 2014-01-13), p. 45-56

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In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 211, No. 1 ( 2014-01-13), p. 45-56

Abstract: We have assessed the role of B lymphocyte stimulator (BLyS) and its receptors in the germinal center (GC) reaction and affinity maturation. Despite ample BLyS retention on B cells in follicular (FO) regions, the GC microenvironment lacks substantial BLyS. This reflects IL-21–mediated down-regulation of the BLyS receptor TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) on GC B cells, thus limiting their capacity for BLyS binding and retention. Within the GC, FO helper T cells (TFH cells) provide a local source of BLyS. Whereas T cell–derived BLyS is dispensable for normal GC cellularity and somatic hypermutation, it is required for the efficient selection of high affinity GC B cell clones. These findings suggest that during affinity maturation, high affinity clones rely on TFH-derived BLyS for their persistence.

Type of Medium: Online Resource

ISSN: 1540-9538 , 0022-1007

URL: Article

DOI: 10.1084/jem.20130505

RVK:

XA 10000

Language: English

Publisher: Rockefeller University Press

Publication Date: 2014

detail.hit.zdb_id: 1477240-1

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Cutting Edge: Dendritic Cell-Restricted Antigen Presentation Initiates the Follicular Helper T Cell Program but Cannot Complete Ultimate Effector Differentiation

Goenka, Radhika ; Barnett, Lisa G. ; Silver, Jonathan S. ; [et al.]

The American Association of Immunologists ; 2011

In: The Journal of Immunology Vol. 187, No. 3 ( 2011-08-01), p. 1091-1095

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 187, No. 3 ( 2011-08-01), p. 1091-1095

Abstract: Follicular helper T (TFH) cells are critical for germinal center (GC) formation. The processes that drive their generation and effector potential remain unclear. In this study, we define requirements for MHC class II APCs in murine TFH cell formation by either transiently ablating or restricting Ag presentation to dendritic cells (DCs). We find that cognate interactions with DCs are necessary and sufficient to prime CD4+ T cells toward a CXCR5+ICOS+Bcl6+ TFH cell intermediate. However, in the absence of additional APCs, these TFH cells fail to produce IL-21. Furthermore, in vitro priming of naive T cells by B cells engenders optimal production of IL-21, which induces a GC B cell transcriptional profile. These results support a multistep model for effector TFH cell priming and GC initiation, in which DCs are necessary and sufficient to induce a TFH cell intermediate that requires additional interactions with distinct APCs for full effector function.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.1100853

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2011

detail.hit.zdb_id: 1475085-5

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T. brucei Infection Reduces B Lymphopoiesis in Bone Marrow and Truncates Compensatory Splenic Lymphopoiesis through Transitional B-Cell Apoptosis

Bockstal, Viki ; Guirnalda, Patrick ; Caljon, Guy ; [et al.]

Public Library of Science (PLoS) ; 2011

In: PLoS Pathogens Vol. 7, No. 6 ( 2011-6-30), p. e1002089-

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In: PLoS Pathogens, Public Library of Science (PLoS), Vol. 7, No. 6 ( 2011-6-30), p. e1002089-

Type of Medium: Online Resource

ISSN: 1553-7374

URL: Article

DOI: 10.1371/journal.ppat.1002089

DOI: 10.1371/journal.ppat.1002089.g001

DOI: 10.1371/journal.ppat.1002089.g002

DOI: 10.1371/journal.ppat.1002089.g003

DOI: 10.1371/journal.ppat.1002089.g004

DOI: 10.1371/journal.ppat.1002089.g005

DOI: 10.1371/journal.ppat.1002089.g006

DOI: 10.1371/journal.ppat.1002089.g007

DOI: 10.1371/journal.ppat.1002089.g008

DOI: 10.1371/journal.ppat.1002089.g009

DOI: 10.1371/journal.ppat.1002089.t001

DOI: 10.1371/journal.ppat.1002089.s001

DOI: 10.1371/journal.ppat.1002089.s002

DOI: 10.1371/journal.ppat.1002089.s003

DOI: 10.1371/journal.ppat.1002089.s004

DOI: 10.1371/journal.ppat.1002089.s005

DOI: 10.1371/journal.ppat.1002089.s006

DOI: 10.1371/journal.ppat.1002089.s007

DOI: 10.1371/journal.ppat.1002089.s008

DOI: 10.1371/journal.ppat.1002089.s009

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2011

detail.hit.zdb_id: 2205412-1

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