Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses

Resistance to several prevalent infectious diseases requires both cellular and humoral immune responses. T cell immunity is initiated by mature dendritic cells (DCs) in lymphoid organs, whereas humoral responses to most antigens require further collaboration between primed, antigen-specific helper T cells and naive or memory B cells. To determine whether antigens delivered to DCs in lymphoid organs induce T cell help for antibody responses, we targeted a carrier protein, ovalbumin (OVA), to DCs in the presence of a maturation stimulus and assayed for antibodies to a hapten, (4-hydroxy-3-nitrophenyl) acetyl (NP), after boosting with OVA-NP. A single DC-targeted immunization elicited long-lived T cell helper responses to the carrier protein, leading to large numbers of antibody-secreting cells and high titers of high-affinity antihapten immunoglobulin Gs. Small doses of DC-targeted OVA induced higher titers and a broader spectrum of anti-NP antibody isotypes than large doses of OVA in alum adjuvant. Similar results were obtained when the circumsporozoite protein of Plasmodium yoelii was delivered to DCs. We conclude that antigen targeting to DCs combined with a maturation stimulus produces broad-based and long-lived T cell help for humoral immune responses.

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Augmentation of in vitro humoral immune responses in the mouse by an antibody to IgD.

Journal of Experimental Medicine ◽

10.1084/jem.152.3.493 ◽

1980 ◽

Vol 152 (3) ◽

pp. 493-506 ◽

Cited By ~ 10

Author(s):

F D Finkelham ◽

V L Woods ◽

S B Wilburn ◽

J J Mond ◽

K E Stein ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Total Serum ◽

Adjuvant Effect ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Almost All ◽

T Cell Help

Heterologous anti-delta-chain antibodies have an adjuvant effect on specific in vivo humoral immune responses to simultaneously, or subsequently, injected antigens in the rat and rhesus monkey. We have used a hybridoma-secreted antibody that binds murine delta-chain of the allotype (4.22aM delta a) to study this phenomenon in the mouse and to investigate the mechanism of this effect. Injection of 4.22aM delta a into BALB/c mice removes almost all surface IgD (sIgD) from splenic B lymphocites. sIgD does not reappear until the serum level of 4.22aM delta a decreased 5-7 d after injection. 4.22aM delta a fails to induce detectable proliferation or to raise total serum Ig levels substantially above control values. However, 4.22aM dalta a injected 24 h before antigen elicits an approximately twofold enhancement of serum IgM and a 3- to 10-fold enhancement of serum IgG anti-trintriphenyl (TNP) antibodies in response to immunization with optimal doses of TNP-Ficoll or TNP-sheep red blood cells (TNP-SRBC). 4.22aM delta a injected 1 wk before or 3 d after TNP-SRBC, however, has no effect on IgG anti-TNP levels. The adjuvant effect of anti-delta-chain antibody was markedly decreased when suboptimal antigen doses were used. Furthermore, even in the case of TNP-Ficoll, a relatively T-independent antigen, the ability of 4.22aM dalta a to enhance the anti-TNP antibody response was T cell dependent. Our data suggest that the binding of anti-delta-chain antibody to cell sIgD may partially activate B lymphocytes and make them more capable of differentiating into antibody-secreting cells when stimulated by antigen-specific T cell help.

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Glycopeptide epitope facilitates HIV-1 envelope specific humoral immune responses by eliciting T cell help

Nature Communications ◽

10.1038/s41467-020-16319-0 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Lina Sun ◽

Amy V. Paschall ◽

Dustin R. Middleton ◽

Mayumi Ishihara ◽

Ahmet Ozdilek ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Humoral Immune ◽

Humoral Immune Responses ◽

T Cell Help ◽

Hiv 1

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Mice Deficient for the Ecto-Nicotinamide Adenine Dinucleotide Glycohydrolase CD38 Exhibit Altered Humoral Immune Responses

Blood ◽

10.1182/blood.v92.4.1324 ◽

1998 ◽

Vol 92 (4) ◽

pp. 1324-1333 ◽

Cited By ~ 143

Author(s):

Debra A. Cockayne ◽

Tony Muchamuel ◽

J. Christopher Grimaldi ◽

Hélène Muller-Steffner ◽

Troy D. Randall ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

B Cell ◽

Nicotinamide Adenine Dinucleotide ◽

Antibody Responses ◽

Nicotinamide Adenine ◽

Humoral Immune ◽

Nad Glycohydrolase ◽

Humoral Immune Responses

Abstract CD38 is a membrane-associated ecto-nicotinamide adenine dinucleotide (NAD+) glycohydrolase that is expressed on multiple hematopoietic cells. The extracellular domain of CD38 can mediate the catalysis of NAD+ to cyclic adenosine diphosphoribose (cADPR), a Ca2+-mobilizing second messenger, adenosine diphosphoribose (ADPR), and nicotinamide. In addition to its enzymatic properties, murine CD38 has been shown to act as a B-cell coreceptor capable of modulating signals through the B-cell antigen receptor. To investigate the in vivo physiological function(s) of this novel class of ectoenzyme we generated mice carrying a null mutation in the CD38 gene. CD38−/− mice showed a complete loss of tissue-associated NAD+ glycohydrolase activity, showing that the classical NAD+ glycohydrolases and CD38 are likely identical. Although murine CD38 is expressed on hematopoietic stem cells as well as on committed progenitors, we show that CD38 is not required for hematopoiesis or lymphopoiesis. However, CD38−/− mice did exhibit marked deficiencies in antibody responses to T-cell–dependent protein antigens and augmented antibody responses to at least one T-cell–independent type 2 polysaccharide antigen. These data suggest that CD38 may play an important role in vivo in regulating humoral immune responses. © 1998 by The American Society of Hematology.

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Role of Interleukin-23-Dependent Antifungal Immune Responses in Dendritic Cell-Vaccinated Mice

Infection and Immunity ◽

10.1128/iai.05163-11 ◽

2011 ◽

Vol 79 (9) ◽

pp. 3778-3783 ◽

Cited By ~ 3

Author(s):

Mingquan Zheng ◽

Rekha R. Rapaka ◽

Amy C. Yu ◽

Judd E. Shellito ◽

Jay K. Kolls

Keyword(s):

T Cell ◽

Immune Responses ◽

Recombinant Adenovirus ◽

Cd40 Ligand ◽

Antibody Responses ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Interleukin 23 ◽

Deficient Mice

ABSTRACTCD40 ligand (CD40L) transduction of antigen-pulsed dendritic cells (DCs) can result in antigen-specific humoral immune responses even in CD4+T-cell-depleted settings. Here, we show that CD40L transduction of DCs results in the induction of interleukin-12p40 (IL-12p40), IL-12p70, and IL-23. Using DCs that were deficient in IL-12p40, IL-12p35, or IL-23p19, we show that these molecules are dispensable for primary IgG1 responses toPneumocystis, but IgG2c was dependent on IL-12p40 and IL-23p19 but not IL-12p35. Antigen-specific recall responses in CD4-deficient mice were critically dependent on IL-12p40 and IL-23p19 expression in DCs and were not affected by the lack of IL-12p35. To confirm that this defect in recall was due to IL-23, transduction of IL-12p40−/−DCs with a recombinant adenovirus expressing functional IL-23 restored recall responses in DC-vaccinated CD4-deficient mice. These data show that DC-produced IL-23 is critical for vaccine-induced antigen-specific IgG2c and recall antibody responses in the setting of CD4+T-cell depletion.

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Mice Deficient for the Ecto-Nicotinamide Adenine Dinucleotide Glycohydrolase CD38 Exhibit Altered Humoral Immune Responses

Blood ◽

10.1182/blood.v92.4.1324.416k26_1324_1333 ◽

1998 ◽

Vol 92 (4) ◽

pp. 1324-1333 ◽

Cited By ~ 5

Author(s):

Debra A. Cockayne ◽

Tony Muchamuel ◽

J. Christopher Grimaldi ◽

Hélène Muller-Steffner ◽

Troy D. Randall ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

B Cell ◽

Nicotinamide Adenine Dinucleotide ◽

Antibody Responses ◽

Nicotinamide Adenine ◽

Humoral Immune ◽

Nad Glycohydrolase ◽

Humoral Immune Responses

CD38 is a membrane-associated ecto-nicotinamide adenine dinucleotide (NAD+) glycohydrolase that is expressed on multiple hematopoietic cells. The extracellular domain of CD38 can mediate the catalysis of NAD+ to cyclic adenosine diphosphoribose (cADPR), a Ca2+-mobilizing second messenger, adenosine diphosphoribose (ADPR), and nicotinamide. In addition to its enzymatic properties, murine CD38 has been shown to act as a B-cell coreceptor capable of modulating signals through the B-cell antigen receptor. To investigate the in vivo physiological function(s) of this novel class of ectoenzyme we generated mice carrying a null mutation in the CD38 gene. CD38−/− mice showed a complete loss of tissue-associated NAD+ glycohydrolase activity, showing that the classical NAD+ glycohydrolases and CD38 are likely identical. Although murine CD38 is expressed on hematopoietic stem cells as well as on committed progenitors, we show that CD38 is not required for hematopoiesis or lymphopoiesis. However, CD38−/− mice did exhibit marked deficiencies in antibody responses to T-cell–dependent protein antigens and augmented antibody responses to at least one T-cell–independent type 2 polysaccharide antigen. These data suggest that CD38 may play an important role in vivo in regulating humoral immune responses. © 1998 by The American Society of Hematology.

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CD8α− Dendritic Cells Induce Antigen-Specific T Follicular Helper Cells Generating Efficient Humoral Immune Responses

Cell Reports ◽

10.1016/j.celrep.2015.05.042 ◽

2015 ◽

Vol 11 (12) ◽

pp. 1929-1940 ◽

Cited By ~ 40

Author(s):

Changsik Shin ◽

Jae-A Han ◽

Hyein Koh ◽

Bongseo Choi ◽

Yongbin Cho ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

T Follicular Helper Cells ◽

Humoral Immune ◽

Helper Cells ◽

Humoral Immune Responses ◽

Follicular Helper

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mRNA vaccination in people over 80 years of age induces strong humoral immune responses against SARS-CoV-2 with cross neutralization of P.1 Brazilian variant

eLife ◽

10.7554/elife.69375 ◽

2021 ◽

Vol 10 ◽

Author(s):

Helen Parry ◽

Gokhan Tut ◽

Rachel Bruton ◽

Sian Faustini ◽

Christine Stephens ◽

...

Keyword(s):

Immune Responses ◽

Cellular Response ◽

Humoral Response ◽

Antibody Responses ◽

Vaccine Platform ◽

Humoral Immune ◽

Vaccine Responses ◽

Cellular Immune Responses ◽

Humoral Immune Responses ◽

Cellular Immune

Age is the major risk factor for mortality after SARS-CoV-2 infection and older people have received priority consideration for COVID-19 vaccination. However, vaccine responses are often suboptimal in this age group and few people over the age of 80 years were included in vaccine registration trials. We determined the serological and cellular response to spike protein in 100 people aged 80–96 years at 2 weeks after the second vaccination with the Pfizer BNT162b2 mRNA vaccine. Antibody responses were seen in every donor with high titers in 98%. Spike-specific cellular immune responses were detectable in only 63% and correlated with humoral response. Previous SARS-CoV-2 infection substantially increased antibody responses after one vaccine and antibody and cellular responses remained 28-fold and 3-fold higher, respectively, after dual vaccination. Post-vaccine sera mediated strong neutralization of live Victoria infection and although neutralization titers were reduced 14-fold against the P.1 variant first discovered in Brazil they remained largely effective. These data demonstrate that the mRNA vaccine platform delivers strong humoral immunity in people up to 96 years of age and retains broad efficacy against the P.1 variant of concern.

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Over‐expression of p190Rho GEF enhances B‐cell activation and germinal center formation in T‐cell‐dependent humoral immune responses

Immunology and Cell Biology ◽

10.1111/imcb.12286 ◽

2019 ◽

Vol 97 (10) ◽

pp. 877-887 ◽

Cited By ~ 1

Author(s):

Ji Hye Jeong ◽

Yun Jung Ha ◽

So‐Yeon Choi ◽

Jee‐Hae Kim ◽

Yungdae Yun ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

B Cell ◽

Germinal Center ◽

Cell Activation ◽

B Cell Activation ◽

Over Expression ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Germinal Center Formation

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Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa

Science Translational Medicine ◽

10.1126/scitranslmed.aax1880 ◽

2019 ◽

Vol 11 (510) ◽

pp. eaax1880 ◽

Cited By ~ 10

Author(s):

Glenda E. Gray ◽

Ying Huang ◽

Nicole Grunenberg ◽

Fatima Laher ◽

Surita Roux ◽

...

Keyword(s):

South Africa ◽

T Cell ◽

Immune Responses ◽

Hiv Vaccine ◽

Antibody Responses ◽

Vaccine Regimen ◽

Humoral Immune ◽

Immune Correlates ◽

Clade C ◽

Hiv 1

One of the most successful HIV vaccines to date, the RV144 vaccine tested in Thailand, demonstrated correlates of protection including cross-clade V1V2 immunoglobulin G (IgG) breadth, Env-specific CD4+ T cell polyfunctionality, and antibody-dependent cellular cytotoxicity (ADCC) in vaccinees with low IgA binding. The HIV Vaccine Trials Network (HVTN) 097 trial evaluated this vaccine regimen in South Africa, where clade C HIV-1 predominates. We compared cellular and humoral responses at peak and durability immunogenicity time points in HVTN 097 and RV144 vaccinee samples, and evaluated vaccine-matched and cross-clade immune responses. At peak immunogenicity, HVTN 097 vaccinees exhibited significantly higher cellular and humoral immune responses than RV144 vaccinees. CD4+ T cell responses were more frequent in HVTN 097 irrespective of age and sex, and CD4+ T cell Env-specific functionality scores were higher in HVTN 097. Env-specific CD40L+ CD4+ T cells were more common in HVTN 097, with individuals having this pattern of expression demonstrating higher median antibody responses to HIV-1 Env. IgG and IgG3 binding antibody rates and response magnitude to gp120 vaccine– and V1V2 vaccine–matched antigens were higher or comparable in HVTN 097 than in RV144 ADCC, and ADCP functional antibody responses were elicited in HVTN 097. Env-specific IgG and CD4+ Env responses declined significantly over time in both trials. Overall, cross-clade immune responses associated with protection were better than expected in South Africa, suggesting wider applicability of this regimen.

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