Early Development in the Peritoneal Cavity of CD49dhigh Th1 Memory Phenotype CD4+ T Cells with Enhanced B Cell Helper Activity

The BCL-6 gene encoding a nuclear-located Kruppel-type zinc finger protein is rearranged in about 30% diffuse large B-cell lymphomas and is expressed predominantly in normal germinal center B cells and related lymphomas. These findings suggest that BCL-6 may play a role in regulating differentiation of normal germinal center B cells and that its deregulated expression caused by rearrangements may contribute to lymphomagenesis. This prompted us to investigate the expression of the BCL-6 protein in Hodgkin's disease (HD), focusing on the nodular lymphocyte predominance subtype (NLPHD), which differs from classical HD by virtue of the B-cell nature of the malignant cell population (so- called L&H cells) and its relationship with germinal centers. Forty-one HD samples (19 NLPHD, 12 nodular sclerosis, and 10 mixed cellularity) were immunostained with the monoclonal antibodies PG-B6 and PG-B6p that react with a fixative-sensitive and a formalin-resistant epitope on the aminoterminal region of the BCL-6 gene product, respectively. Strong nuclear positivity for the BCL-6 protein was detected in tumor (L&H) cells in all cases of NLPHD. In contrast, BCL-6 was expressed only in a small percentage of Hodgkin and Reed-Sternberg cells in about 30% of classical HD cases. Notably, the nuclei of reactive CD3+/CD4+ T cells nearby to and rosetting around L&H cells in NLPHD were also strongly BCL-6+, but lacked CD40 ligand (CD40L) expression. This staining pattern clearly differed from that of classical HD, whose cellular background was made up of CD3+/CD4+ T cells showing the BCL-6-/CD40L+ phenotype. These results further support the concept that NLPHD is an histogenetically distinct, B-cell-derived subtype of HD and suggest a role for BCL-6 in its development.

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Regulatory CD4+ T Cells Promote B Cell Anergy in Murine Lupus

The Journal of Immunology ◽

10.4049/jimmunol.1302897 ◽

2014 ◽

Vol 192 (9) ◽

pp. 4069-4073 ◽

Cited By ~ 15

Author(s):

Yaoyang Liu ◽

Aijing Liu ◽

Noriko Iikuni ◽

Huji Xu ◽

Fu-Dong Shi ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Cd4 T Cells ◽

Murine Lupus ◽

Cell Anergy ◽

B Cell Anergy

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Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutations

Journal of Experimental Medicine ◽

10.1084/jem.20160576 ◽

2016 ◽

Vol 213 (11) ◽

pp. 2413-2435 ◽

Cited By ~ 53

Author(s):

Yi Wang ◽

Cindy S. Ma ◽

Yun Ling ◽

Aziz Bousfiha ◽

Yildiz Camcioglu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cd4 T Cells ◽

Ex Vivo ◽

Cell Phenotype ◽

Loss Of Function ◽

Inborn Errors

Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell–intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients’ B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.

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Foreign antigen-independent memory-phenotype CD4+ T cells: a new player in innate immunity?

Nature Reviews Immunology ◽

10.1038/nri.2018.13 ◽

2018 ◽

Vol 18 (3) ◽

pp. 1-1 ◽

Cited By ~ 2

Author(s):

Ross M. Kedl ◽

Jason T. White

Keyword(s):

Innate Immunity ◽

T Cells ◽

Cd4 T Cells ◽

Foreign Antigen ◽

Memory Phenotype

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Foreign antigen-independent memory-phenotype CD4+ T cells: a new player in innate immunity?

Nature Reviews Immunology ◽

10.1038/nri.2018.12 ◽

2018 ◽

Vol 18 (3) ◽

pp. 1-1 ◽

Cited By ~ 3

Author(s):

Takeshi Kawabe ◽

Jinfang Zhu ◽

Alan Sher

Keyword(s):

Innate Immunity ◽

T Cells ◽

Cd4 T Cells ◽

Foreign Antigen ◽

Memory Phenotype

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Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2108157118 ◽

2021 ◽

Vol 118 (46) ◽

pp. e2108157118

Author(s):

Kerstin Narr ◽

Yusuf I. Ertuna ◽

Benedict Fallet ◽

Karen Cornille ◽

Mirela Dimitrova ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cd4 T Cells ◽

Memory B Cells ◽

Type I ◽

Clonal Deletion ◽

Cell Immunity ◽

B Cell Immunity

Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)–driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called “decimation,” of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I–driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell–intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell–mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell–based vaccination against persistent viral diseases.

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