Impaired humoral responses to COVID-19 vaccination in patients with lymphoma receiving B-cell directed therapies

ABSTRACT APRIL (a proliferation-inducing ligand) is a member of the tumor necrosis factor (TNF) superfamily. APRIL mRNA shows high levels of expression in tumors of different origin and a low level of expression in normal cells. APRIL shares two TNF receptor family members, TACI and BCMA, with another TNF homolog, BLyS/BAFF. BLyS is involved in regulation of B-cell activation and survival and also binds to a third receptor, BR3/BAFF-R, which is not shared with APRIL. Recombinant APRIL and BLyS induce accumulation of B cells in mice, while BLyS deficiency results in severe B-cell dysfunction. To investigate the physiological role of APRIL, we generated mice that are deficient in its encoding gene. APRIL−/− mice were viable and fertile and lacked any gross abnormality. Detailed histological analysis did not reveal any defects in major tissues and organs, including the primary and secondary immune organs. T- and B-cell development and in vitro function were normal as well, as were T-cell-dependent and -independent in vivo humoral responses to antigenic challenge. These data indicate that APRIL is dispensable in the mouse for proper development. Thus, BLyS may be capable of fulfilling APRIL's main functions.

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Age-related Defects in CD4 T Cell Cognate Helper Function Lead to Reductions in Humoral Responses

Journal of Experimental Medicine ◽

10.1084/jem.20041395 ◽

2004 ◽

Vol 200 (12) ◽

pp. 1613-1622 ◽

Cited By ~ 175

Author(s):

Sheri M. Eaton ◽

Eve M. Burns ◽

Kimberly Kusser ◽

Troy D. Randall ◽

Laura Haynes

Keyword(s):

T Cells ◽

B Cell ◽

Cd4 T Cells ◽

Donor Cell ◽

The Elderly ◽

Transfer Model ◽

Age Related ◽

Wide Range ◽

Helper Function ◽

Humoral Responses

With increasing age, the ability to produce protective antibodies in response to immunization declines, leading to a reduced efficacy of vaccination in the elderly. To examine the effect of age on the cognate function of CD4 T cells, we have used a novel adoptive transfer model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) donors. Upon transfer of aged donor CD4 T cells to young hosts, there was significantly reduced expansion and germinal center (GC) differentiation of the antigen-specific B cell population after immunization. This reduced cognate helper function was seen at all time points and over a wide range of donor cell numbers. In hosts receiving aged CD4 cells, there were also dramatically lower levels of antigen-specific IgG. These age-related defects were not due to defects in migration of the aged CD4 T cells, but may be attributable to reduced CD154 (CD40L) expression. Furthermore, we found that there was no difference in B cell expansion and differentiation or in IgG production when young CD4 T cells were transferred to young or aged hosts. Our results show that, in this model, age-related reductions in the cognate helper function of CD4 T cells contribute significantly to defects in humoral responses observed in aged individuals.

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Complementary Role of CD4+ T Cells in Response to Pneumococcal Polysaccharide Vaccines in Humans

Vaccines ◽

10.3390/vaccines7010018 ◽

2019 ◽

Vol 7 (1) ◽

pp. 18 ◽

Cited By ~ 4

Author(s):

Vibha Jha ◽

Edward N. Janoff

Keyword(s):

T Cells ◽

B Cell ◽

Bloodstream Infections ◽

Capsular Polysaccharides ◽

Protein Antigens ◽

Cell Responses ◽

Populations At Risk ◽

B Cell Responses ◽

Humoral Responses

Bacterial pathogens expressing capsular polysaccharides are common causes of mucosal infections (pneumonia, intestinal), as well as often fatal, invasive infections (meningitis, bloodstream infections) in children and adults worldwide. These chemically simple but structurally complex carbohydrate structures on the bacterial surface confer resistance to recognition and clearance by the immune system through a range of mechanisms. Such recognition of capsular polysaccharides may be reduced by their limited ability to directly stimulate B cells and the T cells that may facilitate these humoral responses. The capsules may promote the evasion of complement deposition and activation and may sterically shield the recognition of other subjacent protein antigens by innate factors. Antibodies to capsular polysaccharides, elicited by infection and vaccines, may overcome these obstacles and facilitate bacterial agglutination at mucosal surfaces, as well as the opsonization and clearance of these organisms in tissues and the systemic compartment. However, the immunogenicity of these antigens may be limited by their lack of direct recognition by T cells ("T-independent" antigens) and their restricted ability to generate effective memory responses. In this review, we consider the mechanisms by which polysaccharides may initiate B cell responses and specific antibody responses and the role of T cells, particularly CD4+ follicular helper (TFH) cells to support this process. In addition, we also consider more recent counterintuitive data that capsular polysaccharides themselves may bind major histocompatibility antigen HLA class II to provide a more physiologic mechanism of T cell enhancement of B cell responses to capsular polysaccharides. Defining the contributions of T cells in the generation of effective humoral responses to the capsular polysaccharides will have important implications for understanding and translating this immunobiology for the development of more effective vaccines, to prevent the morbidity and mortality associated with these common mucosal and invasive pathogens in populations at risk.

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Oxysterol Gradient Generation by Lymphoid Stromal Cells Guides Activated B Cell Movement during Humoral Responses

Immunity ◽

10.1016/j.immuni.2012.06.015 ◽

2012 ◽

Vol 37 (3) ◽

pp. 535-548 ◽

Cited By ~ 121

Author(s):

Tangsheng Yi ◽

Xiaoming Wang ◽

Lisa M. Kelly ◽

Jinping An ◽

Ying Xu ◽

...

Keyword(s):

B Cell ◽

Stromal Cells ◽

Cell Movement ◽

Gradient Generation ◽

Humoral Responses

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Nuclear Factor (NF)-κB2 (p100/p52) Is Required for Normal Splenic Microarchitecture and B Cell–mediated Immune Responses

Journal of Experimental Medicine ◽

10.1084/jem.187.2.185 ◽

1998 ◽

Vol 187 (2) ◽

pp. 185-196 ◽

Cited By ~ 283

Author(s):

Jorge H. Caamaño ◽

Cheryl A. Rizzo ◽

Stephen K. Durham ◽

Debra S. Barton ◽

Carmen Raventós-Suárez ◽

...

Keyword(s):

T Cell ◽

Lymph Nodes ◽

B Cell ◽

Immunological Response ◽

Mutant Mice ◽

T Cell Lymphomas ◽

Normal Spleen ◽

Multiple Myelomas ◽

Spleen And Lymph Nodes ◽

Humoral Responses

The nfkb2 gene is a member of the Rel/NF-κB family of transcription factors. COOH-terminal deletions and rearrangements of this gene have been associated with the development of human cutaneous T cell lymphomas, chronic lymphocytic leukemias, and multiple myelomas. To further investigate the function of NF-κB2, we have generated mutant mice carrying a germline mutation of the nfkb2 gene by homologous recombination. NF-κB2–deficient mice showed a marked reduction in the B cell compartment in spleen, bone marrow, and lymph nodes. Moreover, spleen and lymph nodes of mutant mice presented an altered architecture, characterized by diffuse, irregular B cell areas and the absence of discrete perifollicular marginal and mantle zones; the formation of secondary germinal centers in spleen was also impaired. Proliferation of NF-κB2–deficient B cells was moderately reduced in response to lipopolysaccharide, anti-IgD-dextran, and CD40, but maturation and immunoglobulin switching were normal. However, nfkb2 (−/−) animals presented a deficient immunological response to T cell–dependent and –independent antigens. These findings indicate an important role of NF-κB2 in the maintenance of the peripheral B cell population, humoral responses, and normal spleen architecture.

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Rap1 Is Essential for B-Cell Locomotion, Germinal Center Formation and Normal B-1a Cell Population

Frontiers in Immunology ◽

10.3389/fimmu.2021.624419 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sayaka Ishihara ◽

Tsuyoshi Sato ◽

Risa Sugioka ◽

Ryota Miwa ◽

Haruka Saito ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Specific Antibody ◽

Stromal Cells ◽

Germinal Center ◽

Specific Antibody Production ◽

Humoral Responses ◽

Integrin Regulation ◽

Germinal Center Formation

Integrin regulation by Rap1 is indispensable for lymphocyte recirculation. In mice having B-cell-specific Rap1a/b double knockouts (DKO), the number of B cells in lymph nodes decreased to approximately 4% of that of control mice, and B cells were present in the spleen and blood. Upon the immunization with NP-CGG, DKO mice demonstrated the defective GC formation in the spleen, and the reduced NP-specific antibody production. In vitro, Rap1 deficiency impaired the movement of activated B cells along the gradients of chemoattractants known to be critical for their localization in the follicles. Furthermore, B-1a cells were almost completely absent in the peritoneal cavity, spleen and blood of adult DKO mice, and the number of B-cell progenitor/precursor (B-p) were reduced in neonatal and fetal livers. However, DKO B-ps normally proliferated, and differentiated into IgM+ cells in the presence of IL-7. CXCL12-dependent migration of B-ps on the VCAM-1 was severely impaired by Rap1 deficiency. Immunostaining study of fetal livers revealed defects in the co-localization of DKO B-ps and IL-7-producing stromal cells. This study proposes that the profound effects of Rap1-deficiency on humoral responses and B-1a cell generation may be due to or in part caused by impairments of the chemoattractant-dependent positioning and the contact with stromal cells.

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B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

Frontiers in Immunology ◽

10.3389/fimmu.2021.782558 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kenneth Green ◽

Thomas R. Wittenborn ◽

Cecilia Fahlquist-Hagert ◽

Ewa Terczynska-Dyla ◽

Nina van Campen ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Type I Interferon ◽

Affinity Maturation ◽

Antibody Responses ◽

Type I ◽

Cell Responses ◽

B Cell Responses ◽

Sting Pathway ◽

Humoral Responses

Germinal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signals driving B cell participation in GC responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an important mediator of type I interferon and proinflammatory cytokine responses during infection and cellular stress. Recent studies have reported important roles for STING in B cell responses, including an impact on GC B cells and downstream antibody responses, which could have great consequences for vaccine design and understanding STING-associated interferonopathies. GCs are also involved in untoward reactions to autoantigens in a plethora of autoimmune disorders, and it is generally thought that these responses coopt the mechanisms used in foreign antigen-directed GCs. Here, we set out to investigate the importance of the cGAS-STING pathway in autoreactive B cell responses. In a direct competition scenario in a murine mixed bone marrow chimera model of autoreactive GCs, we find that B cell intrinsic deficiency of cGAS, STING, or the type I interferon receptor IFNAR, does not impair GC participation, whereas Toll-like receptor (TLR)-7 deficiency mediates a near-complete block. Our findings suggest that physiological B cell responses are strictly sustained by signals linked to BCR-mediated endocytosis. This wiring of B cell signals may enable appropriate antibody responses, while at the same time restricting aberrant antibody responses during infections and in autoimmune or autoinflammatory settings.

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Blockade of LAG-3 in PD-L1-Deficient Mice Enhances Clearance of Blood Stage Malaria Independent of Humoral Responses

Frontiers in Immunology ◽

10.3389/fimmu.2020.576743 ◽

2021 ◽

Vol 11 ◽

Author(s):

Raquel Furtado ◽

Laurent Chorro ◽

Natalie Zimmerman ◽

Erik Guillen ◽

Emily Spaulding ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Blood Parasites ◽

Natural Immunity ◽

Inhibitory Receptors ◽

Chronic Infections ◽

Cell Functions ◽

Cell Responses ◽

B Cell Responses ◽

Humoral Responses

T cells expressing high levels of inhibitory receptors such as PD-1 and LAG-3 are a hallmark of chronic infections and cancer. Checkpoint blockade therapies targeting these receptors have been largely validated as promising strategies to restore exhausted T cell functions and clearance of chronic infections and tumors. The inability to develop long-term natural immunity in malaria-infected patients has been proposed to be at least partially accounted for by sustained expression of high levels of inhibitory receptors on T and B lymphocytes. While blockade or lack of PD-1/PD-L1 and/or LAG-3 was reported to promote better clearance of Plasmodium parasites in various mouse models, how exactly blockade of these pathways contributes to enhanced protection is not known. Herein, using the mouse model of non-lethal P. yoelii (Py) infection, we reveal that the kinetics of blood parasitemia as well as CD4+ T follicular helper (TFH) and germinal center (GC) B cell responses are indistinguishable between PD-1-/-, PD-L1-/- and WT mice. Yet, we also report that monoclonal antibody (mAb) blockade of LAG-3 in PD-L1-/- mice promotes accelerated control of blood parasite growth and clearance, consistent with prior therapeutic blockade experiments. However, neither CD4+ TFH and GC B cell responses, nor parasite-specific Ab serum titers and capacity to transfer protection differed. We also found that i) the majority of LAG-3+ cells are T cells, ii) selective depletion of CD4+ but not CD8+ T cells prevents anti-LAG-3-mediated protection, and iii) production of effector cytokines by CD4+ T cells is increased in anti-LAG-3-treated versus control mice. Thus, taken together, these results are consistent with a model in which blockade and/or deficiency of PD-L1 and LAG-3 on parasite-specific CD4+ T cells unleashes their ability to effectively clear blood parasites, independently from humoral responses.

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