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Article ; Online: The spleen: "epicenter" in malaria infection and immunity.

Ghosh, Debopam / Stumhofer, Jason S

2021 Volume 110, Issue 4, Page(s) 753–769

Abstract: The spleen is a complex secondary lymphoid organ that plays a crucial role in controlling blood-stage infection with Plasmodium parasites. It is tasked with sensing and removing parasitized RBCs, erythropoiesis, the activation and differentiation of ... ...

Abstract	The spleen is a complex secondary lymphoid organ that plays a crucial role in controlling blood-stage infection with Plasmodium parasites. It is tasked with sensing and removing parasitized RBCs, erythropoiesis, the activation and differentiation of adaptive immune cells, and the development of protective immunity, all in the face of an intense inflammatory environment. This paper describes how these processes are regulated following infection and recognizes the gaps in our current knowledge, highlighting recent insights from human infections and mouse models.
MeSH term(s)	Animals ; Erythrocytes/parasitology ; Hematopoiesis ; Humans ; Immunity ; Malaria/immunology ; Malaria/parasitology ; Malaria/prevention & control ; Plasmodium/physiology ; Spleen/immunology ; Spleen/parasitology ; Spleen/pathology
Language	English
Publishing date	2021-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1002/JLB.4RI1020-713R
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Article ; Online: Bhlhe40 limits early IL-10 production from CD4

O'Neal, Kara A / Zeltner, Sheldon L / Foscue, Camille L / Stumhofer, Jason S

Infection and immunity

2023 Volume 91, Issue 11, Page(s) e0036723

Abstract: The cytokine IL-10 suppresses T-cell-mediated immunity, which is required to control infection ... ...

Abstract	The cytokine IL-10 suppresses T-cell-mediated immunity, which is required to control infection with
MeSH term(s)	Mice ; Animals ; Interleukin-10 ; Plasmodium yoelii ; Cytokines ; Interferon-gamma ; T-Lymphocytes, Regulatory/metabolism ; Mice, Inbred C57BL ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Basic Helix-Loop-Helix Transcription Factors/genetics
Chemical Substances	Interleukin-10 (130068-27-8) ; Cytokines ; Interferon-gamma (82115-62-6) ; Bhlhe40 protein, mouse ; Homeodomain Proteins ; Basic Helix-Loop-Helix Transcription Factors
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/iai.00367-23
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Article ; Online: ICOS signaling promotes a secondary humoral response after re-challenge with Plasmodium chabaudi chabaudi AS.

Latham, Leah E / Wikenheiser, Daniel J / Stumhofer, Jason S

PLoS pathogens

2020 Volume 16, Issue 4, Page(s) e1008527

Abstract: The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS ... ...

Abstract	The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS signaling in secondary immune responses is largely unexplored. Here we show that memory T cell formation and maintenance are influenced by persistent infection with P. chabaudi chabaudi AS infection, as memory T cell numbers decline in wild-type and Icos-/- mice after drug-clearance. Following drug-clearance Icos-/- mice display a relapsing parasitemia that occurs more frequently and with higher peaks compared to wild-type mice after re-challenge. The secondary immune response in Icos-/- mice is characterized by significant impairment in the expansion of effector cells with a Tfh-like phenotype, which is associated with a diminished and delayed parasite-specific Ab response and the absence of germinal centers. Similarly, the administration of an anti-ICOSL antagonizing antibody to wild-type mice before and after reinfection with P. c. chabaudi AS leads to an early defect in Tfh cell expansion and parasite-specific antibody production, confirming a need for ICOS-ICOSL interactions to promote memory B cell responses. Furthermore, adoptive transfer of central memory T (TCM) cells from wild-type and Icos-/- mice into tcrb-/- mice to directly evaluate the ability of TCM cells to give rise to Tfh cells revealed that TCM cells from wild-type mice acquire a mixed Th1- and Tfh-like phenotype after P. c. chabaudi AS infection. While TCM cells from Icos-/- mice expand and display markers of activation to a similar degree as their WT counterparts, they displayed a reduced capacity to upregulate markers indicative of a Tfh cell phenotype, resulting in a diminished humoral response. Together these findings verify that ICOS signaling in memory T cells plays an integral role in promoting T cell effector responses during secondary infection with P. c. chabaudi AS.
MeSH term(s)	Adoptive Transfer ; Animals ; B-Lymphocytes/immunology ; Cell Differentiation/immunology ; Germinal Center/immunology ; Immunity, Humoral/immunology ; Immunologic Memory ; Inducible T-Cell Co-Stimulator Protein/immunology ; Inducible T-Cell Co-Stimulator Protein/metabolism ; Lymphocyte Activation/immunology ; Malaria/immunology ; Malaria/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Plasmodium chabaudi/metabolism ; Plasmodium chabaudi/pathogenicity ; Signal Transduction ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/metabolism
Chemical Substances	ICOS protein, human ; Icos protein, mouse ; Inducible T-Cell Co-Stimulator Protein
Language	English
Publishing date	2020-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1008527
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Article ; Online: ICOS Expression Is Required for Maintenance but Not the Formation of Germinal Centers in the Spleen in Response to Plasmodium yoelii Infection.

O'Neal, Kara A / Latham, Leah E / Ntirandekura, Enatha / Foscue, Camille L / Stumhofer, Jason S

Infection and immunity

2022 Volume 90, Issue 3, Page(s) e0046821

Abstract: Inducible T cell costimulator (ICOS) plays a key role in the differentiation and maintenance of follicular helper T (Tfh) cells and, thus, germinal center (GC) formation. Previously, our laboratory showed in a Plasmodium chabaudi infection model ... ...

Abstract	Inducible T cell costimulator (ICOS) plays a key role in the differentiation and maintenance of follicular helper T (Tfh) cells and, thus, germinal center (GC) formation. Previously, our laboratory showed in a Plasmodium chabaudi infection model that
MeSH term(s)	Animals ; B-Lymphocytes ; Germinal Center/metabolism ; Inducible T-Cell Co-Stimulator Protein/metabolism ; Malaria ; Mice ; Mice, Inbred C57BL ; Plasmodium yoelii ; Spleen/metabolism ; T-Lymphocytes, Helper-Inducer
Chemical Substances	Icos protein, mouse ; Inducible T-Cell Co-Stimulator Protein
Language	English
Publishing date	2022-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.00468-21
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Article ; Online: IgM

Brown, Susie L / Bauer, Jonathan J / Lee, Juhyung / Ntirandekura, Enatha / Stumhofer, Jason S

Journal of leukocyte biology

2022 Volume 112, Issue 5, Page(s) 1115–1135

Abstract: Memory B cells (MBCs) are essential for maintaining long-term humoral immunity to infectious organisms, including Plasmodium. MBCs are a heterogeneous population whose function can be dictated by isotype or expression of particular surface proteins. Here, ...

Abstract	Memory B cells (MBCs) are essential for maintaining long-term humoral immunity to infectious organisms, including Plasmodium. MBCs are a heterogeneous population whose function can be dictated by isotype or expression of particular surface proteins. Here, aided by antigen-specific B-cell tetramers, MBC populations were evaluated to discern their phenotype and function in response to infection with a nonlethal strain of P. yoelii. Infection of mice with P. yoelii 17X resulted in 2 predominant MBC populations: somatically hypermutated isotype-switched (IgM
MeSH term(s)	Animals ; Mice ; B7-1 Antigen ; Cytidine Deaminase ; Germinal Center ; Immunoglobulin G ; Immunoglobulin M ; Immunologic Memory ; Memory B Cells/immunology ; Plasmodium yoelii ; Malaria/immunology
Chemical Substances	B7-1 Antigen ; Cytidine Deaminase (EC 3.5.4.5) ; Immunoglobulin G ; Immunoglobulin M
Language	English
Publishing date	2022-06-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1002/JLB.4A0921-523R
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Article: ICOS Co-Stimulation: Friend or Foe?

Wikenheiser, Daniel J / Stumhofer, Jason S

Frontiers in immunology

2016 Volume 7, Page(s) 304

Abstract: Over the last 15 years, the inducible T cell co-stimulator (ICOS) has been implicated in various immune outcomes, including the induction and regulation of Th1, Th2, and Th17 immunity. In addition to its role in directing effector T cell differentiation, ...

Abstract	Over the last 15 years, the inducible T cell co-stimulator (ICOS) has been implicated in various immune outcomes, including the induction and regulation of Th1, Th2, and Th17 immunity. In addition to its role in directing effector T cell differentiation, ICOS has also been consistently linked with the induction of thymus-dependent (TD) antibody (Ab) responses and the germinal center (GC) reaction. ICOS co-stimulation, therefore, appears to play a complex role in dictating the course of adaptive immunity. In this article, we summarize the initial characterization of ICOS and its relationship with the related co-stimulatory molecule CD28. We then address the contribution of ICOS in directing an effector T cell response, and ultimately disease outcome, against various bacterial, viral, and parasitic infections. Next, we assess ICOS in the context of TD Ab responses, connecting ICOS signaling to follicular helper T cell differentiation and its role in the GC reaction. Finally, we address the link between ICOS and human autoimmune disorders and evaluate potential therapies aiming to mitigate disease progression by modulating ICOS signaling.
Language	English
Publishing date	2016
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2016.00304
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Article ; Online: The Immunobiology of the Interleukin-12 Family: Room for Discovery.

Tait Wojno, Elia D / Hunter, Christopher A / Stumhofer, Jason S

Immunity

2019 Volume 50, Issue 4, Page(s) 851–870

Abstract: The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the ... ...

Abstract	The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Autoimmune Diseases/therapy ; Cytokines/antagonists & inhibitors ; Cytokines/genetics ; Cytokines/immunology ; Humans ; Immunity, Cellular ; Inflammation/immunology ; Interleukin-12/antagonists & inhibitors ; Interleukin-12/genetics ; Interleukin-12/immunology ; Interleukin-27/therapeutic use ; Lymphocyte Subsets/immunology ; Lymphopoiesis ; Mice ; Mice, Knockout ; Multigene Family/genetics ; Multigene Family/immunology ; Neoplasms, Experimental/immunology ; Neoplasms, Experimental/therapy ; Protein Subunits ; Structure-Activity Relationship
Chemical Substances	Cytokines ; Interleukin-27 ; Protein Subunits ; Interleukin-12 (187348-17-0)
Language	English
Publishing date	2019-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2019.03.011
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Article: Do you see what I see: Recognition of protozoan parasites by Toll-like receptors.

Ghosh, Debopam / Stumhofer, Jason S

Current immunology reviews

2014 Volume 9, Issue 3, Page(s) 129–140

Abstract: Toll-like receptors (TLRs) are important for recognizing a variety of pathogens, including protozoan parasites, and initiating innate immune responses against them. TLRs are localized on the cell surface as well as in the endosome, and are implicated in ... ...

Abstract	Toll-like receptors (TLRs) are important for recognizing a variety of pathogens, including protozoan parasites, and initiating innate immune responses against them. TLRs are localized on the cell surface as well as in the endosome, and are implicated in innate sensing of these parasites. In this review, we will discuss recent findings on the identification of parasite-derived pathogen associated molecular patterns and the TLRs that bind them. The role of these TLRs in initiating the immune response against protozoan parasitic infections
Language	English
Publishing date	2014-05-14
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2274820-9
ISSN	1875-631X ; 1573-3955
ISSN (online)	1875-631X
ISSN	1573-3955
DOI	10.2174/1573395509666131203225929
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Article: Parasites: what are they good for?

Stumhofer, Jason S / Loke, P'ng

Current immunology reviews

2014 Volume 9, Issue 3, Page(s) 120–128

Abstract: Parasitic diseases caused by helminth and protozoan infections remain one of the largest global public health problems for mankind. While natural immunity in man is rare or slow to develop for many parasites, the immune response is capable of recognizing ...

Abstract	Parasitic diseases caused by helminth and protozoan infections remain one of the largest global public health problems for mankind. While natural immunity in man is rare or slow to develop for many parasites, the immune response is capable of recognizing and responding to infection by utilizing a number of different immunological mechanisms. This special topics journal issue examines many of the key findings in the recent literature regarding the immune response against helminth and protozoan infections, as well as highlighting areas in which our current knowledge falls short. The question of how we can tailor immune responses to prevent or reduce disease burden is a burning question within the field of immunoparasitology.
Language	English
Publishing date	2014-02-13
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2274820-9
ISSN	1875-631X ; 1573-3955
ISSN (online)	1875-631X
ISSN	1573-3955
DOI	10.2174/1573395509666131203001449
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Article: Intrinsic p53 Activation Restricts Gammaherpesvirus-Driven Germinal Center B Cell Expansion during Latency Establishment.

Owens, Shana M / Sifford, Jeffrey M / Li, Gang / Murdock, Steven J / Salinas, Eduardo / Manzano, Mark / Ghosh, Debopam / Stumhofer, Jason S / Forrest, J Craig

bioRxiv : the preprint server for biology

2023

Abstract: Gammaherpesviruses (GHV) are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), this is accomplished through a viral gene-expression program ... ...

Abstract	Gammaherpesviruses (GHV) are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center (GC) B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of GHV pathogenesis, we demonstrate Importance: Gammaherpesviruses cause lifelong infections of their hosts, commonly referred to as latency, that can lead to cancer. Latency establishment benefits from the functions of viral proteins that augment and amplify B cell activation, proliferation, and differentiation signals. In uninfected cells, off-schedule cellular differentiation would typically trigger anti-proliferative responses by effector proteins known as tumor suppressors. However, tumor suppressor responses to gammaherpesvirus manipulation of cellular processes remain understudied, especially those that occur during latency establishment in a living organism. Here we identify p53, a tumor suppressor commonly mutated in cancer, as a host factor that limits virus-driven B cell proliferation and differentiation, and thus, viral colonization of a host. We demonstrate that p53 activation occurs in response to viral latency proteins that induce B cell activation. This work informs a gap in our understanding of intrinsic cellular defense mechanisms that restrict lifelong GHV infection.
Language	English
Publishing date	2023-11-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.31.563188
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