T and B cell responses to chimeric proteins containing heterologous T helper epitopes inserted at different positions

Major histocompatibility complex-restricted helper T cell clones against "minor" antigens expressed on B cell and macrophage surfaces, when confronted with appropriate T cell-depleted spleen cells, are induced to proliferation and, in turn, activate "target-responder" B cells to polyclonal growth and maturation. Irradiation of helper cell populations, however, demonstrates that their effector functions (and B lymphocyte responses) are independent of proliferative activity. Adherent cell depletion on Sephadex G10 columns, while completely abrogating helper T cell proliferation, does not abolish helper cell-induced B cell responses, demonstrating a remarkable quantitative difference in macrophage requirements for the growth of these two cell types. Because significant B cell responses are detected upon interaction with primed helper T cells under conditions of extreme macrophage depletion, we conclude that the role of macrophages in T-B cell cooperation is limited to expansion of optimal numbers of helper T lymphocytes. It follows that activated helper cells can autonomously produce all B cell-specific growth and maturation factors mediating cooperative antibody responses. In contrast, the profound reduction of LPS-induced responses upon macrophage depletion suggests accessory cell production of such factors in thymus-independent B cell growth and/or maturation.

Download Full-text

Age-Related Development of Human Memory T-Helper and B-Cell Responses toward Parainfluenza Virus Type-1

Virology ◽

10.1006/viro.1994.1665 ◽

1994 ◽

Vol 205 (2) ◽

pp. 453-461 ◽

Cited By ~ 28

Author(s):

F.Suzette Smith ◽

Allen Portner ◽

Robert J. Leggiadro ◽

E.Victoria Turner ◽

Julia L. Hurwitz

Keyword(s):

B Cell ◽

Virus Type ◽

Human Memory ◽

Parainfluenza Virus ◽

T Helper ◽

Cell Responses ◽

Age Related ◽

Related Development ◽

B Cell Responses

Download Full-text

Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site

Journal of Virology ◽

10.1128/jvi.00811-17 ◽

2017 ◽

Vol 91 (19) ◽

Cited By ~ 4

Author(s):

Willy M. J. M. Bogers ◽

Susan W. Barnett ◽

Herman Oostermeijer ◽

Ivonne G. Nieuwenhuis ◽

Niels Beenhakker ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Binding Site ◽

T Helper ◽

Cell Responses ◽

Cd4 Receptor ◽

Cd4 Binding Site ◽

B Cell Responses ◽

Hiv Envelope ◽

Hiv 1

ABSTRACT Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens (Ag) for more long-lived, efficacious HIV-1 vaccine-induced B-cell responses. HIV-1 Env gp140 (native or uncleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells results in anergic effects on T-cell recruitment and consequently a lack of strong, robust, and durable B-memory responses. To test this hypothesis, we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3-kDa CD4 miniprotein mimetic, serving to block ligation of gp140 on CD4+ T cells while preserving CD4-inducible (CDi) neutralizing epitopes targeted by antibody-dependent cellular cytotoxicity (ADCC) effector responses. Importantly, immunization of rhesus macaques consistently gave superior B-cell (P < 0.001) response kinetics and superior ADCC (P < 0.014) in a group receiving the CD4bs-occluded vaccine compared to those of animals immunized with gp140. Of the cytokines examined, Ag-specific interleukin-4 (IL-4) T-helper enzyme-linked immunosorbent spot (ELISpot) assays of the CD4bs-occluded group increased earlier (P = 0.025) during the inductive phase. Importantly, CD4bs-occluded gp140 antigen induced superior B-cell and ADCC responses, and the elevated B-cell responses proved to be remarkably durable, lasting more than 60 weeks postimmunization. IMPORTANCE Attempts to develop HIV vaccines capable of inducing potent and durable B-cell responses have been unsuccessful until now. Antigen-specific B-cell development and affinity maturation occurs in germinal centers in lymphoid follicles through a critical interaction between B cells and T follicular helper cells. The HIV envelope binds the CD4 receptor on T cells as soluble shed antigen or as antigen-antibody complexes, causing impairment in the activation of these specialized CD4-positive T cells. We proposed that CD4-binding impairment is partly responsible for the relatively poor B-cell responses to HIV envelope-based vaccines. To test this hypothesis, we blocked the CD4 binding site of the envelope antigen and compared it to currently used unblocked envelope protein. We found superior and durable B-cell responses in macaques vaccinated with an occluded CD4 binding site on the HIV envelope antigen, demonstrating a potentially important new direction in future design of new HIV vaccines.

Download Full-text

Effect of Immunosuppression on T-Helper 2 and B-Cell Responses to Influenza Vaccination

The Journal of Infectious Diseases ◽

10.1093/infdis/jiv015 ◽

2015 ◽

Vol 212 (1) ◽

pp. 137-146 ◽

Cited By ~ 8

Author(s):

A. Egli ◽

A. Humar ◽

L. A. Widmer ◽

L. F. Lisboa ◽

D. M. Santer ◽

...

Keyword(s):

Influenza Vaccination ◽

B Cell ◽

T Helper ◽

T Helper 2 ◽

Cell Responses ◽

B Cell Responses

Download Full-text

P70W1-2 Schistosome infection stimulates host CD4^+ T helper cell and B cell responses against a novel egg antigen thioredoxin peroxidase

Medical Entomology and Zoology ◽

10.7601/mez.52.95_2 ◽

2001 ◽

Vol 52 (Supplement) ◽

pp. 95

Author(s):

Hiroko ASAHI ◽

Douglas J. Botkin ◽

Miguel J. Stadecker ◽

David L. Williams

Keyword(s):

B Cell ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Schistosome Infection ◽

Cell Responses ◽

Thioredoxin Peroxidase ◽

B Cell Responses ◽

Egg Antigen

Download Full-text

Schistosome Infection Stimulates Host CD4+ T Helper Cell and B-Cell Responses against a Novel Egg Antigen, Thioredoxin Peroxidase

Infection and Immunity ◽

10.1128/iai.69.2.1134-1141.2001 ◽

2001 ◽

Vol 69 (2) ◽

pp. 1134-1141 ◽

Cited By ~ 47

Author(s):

David L. Williams ◽

Hiroko Asahi ◽

Douglas J. Botkin ◽

Miguel J. Stadecker

Keyword(s):

B Cell ◽

Interleukin 2 ◽

Granuloma Formation ◽

T Helper ◽

Cell Responses ◽

Th Cell ◽

Thioredoxin Peroxidase ◽

Ifn Γ ◽

B Cell Responses ◽

Egg Antigen

ABSTRACT Egg granuloma formation during schistosome infections is mediated by CD4+ T helper (Th) cells sensitized to egg antigens; however, most of the relevant sensitizing egg antigens are still unknown. Here we show that schistosome thioredoxin peroxidase (TPx)-1 is a novel T- and B-cell egg antigen in schistosome-infected mice. CD4+ Th cell responses to fractionated egg components identified a significant response against a 26-kDa antigen; a partial amino acid sequence of this antigen was found to be identical to that of Schistosoma mansoni TPx-1. The native TPx-1 elicited significant proliferative responses as well as gamma interferon (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-5 secretion in CD4+ cells from 8.5-week-infected CBA and C57BL/6 mice. By comparison, recombinant TPx-1 elicited a smaller, more type 1-polarized response, with significant production of IFN-γ and IL-2, less IL-5, and essentially no IL-4. In C57BL/6 mice the responses to TPx-1 were relatively more prominent than that directed against the major egg antigen, Sm-p40, whereas in CBA mice the reverse was true. B-cell responses were also monitored in infected C57BL/6, C3H, CBA, and BALB/c mice. All strains had significant antibody levels against the TPx-1 protein, but the most significant antibody production ensued following parasite oviposition. TPx-1 was localized in eggs and shown to be secreted by eggs. The identification of egg antigens is important to understand the specific basis of granuloma formation in schistosome infections and may prove to be useful in strategies to ameliorate pathological responses.

Download Full-text