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Transient CD4+ T Cell Depletion Results in Delayed Development of Functional Vaccine-Elicited Antibody Responses.

Provine NM, Badamchi-Zadeh A, Bricault CA, Penaloza-MacMaster P, Larocca RA, Borducchi EN, Seaman MS, Barouch DH - J. Virol. (2016)

Bottom Line: Upon CD4(+)T cell recovery, transgene-specific serum IgG antibody titers develop and reach a concentration equivalent to that in undepleted control animals.The paradigm is that helper signals must be provided immediately upon antigen exposure, and their absence results in tolerance against the antigen.These data demonstrate that the time when CD4(+)T cell help signals must be provided is more dynamic and flexible than previously appreciated.

View Article: PubMed Central - PubMed

Affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

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Boosting capacity and functional neutralization capacity of delayed antibody responses that develop following transient CD4+ T cell depletion. (A) C57BL/6 mice were depleted of CD4+ T cells or left untreated, immunized intramuscularly with 1010 vp of Ad26-SIV Env, and boosted 4 months postprime with 1010 vp of Ad5-SIV Env. (B) SIV Env-specific antibody titers prior to and following boosting immunization. (C) Fold change in SIV Env-specific antibody responses pre- to postboost. (D) Serum 50% neutralization capacity (IC50) of tier 1A SIVmac251.TCLA.15 Env-expressing pseudoviruses or a MuLV negative-control pseudovirus. Each dot represents an individual mouse, and the line indicates the mean ± the standard error of the mean (C) or the median (D). The horizontal dotted line denotes the limit of detection for the assay (n = 6 to 8/group pooled from two experiments).
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Figure 3: Boosting capacity and functional neutralization capacity of delayed antibody responses that develop following transient CD4+ T cell depletion. (A) C57BL/6 mice were depleted of CD4+ T cells or left untreated, immunized intramuscularly with 1010 vp of Ad26-SIV Env, and boosted 4 months postprime with 1010 vp of Ad5-SIV Env. (B) SIV Env-specific antibody titers prior to and following boosting immunization. (C) Fold change in SIV Env-specific antibody responses pre- to postboost. (D) Serum 50% neutralization capacity (IC50) of tier 1A SIVmac251.TCLA.15 Env-expressing pseudoviruses or a MuLV negative-control pseudovirus. Each dot represents an individual mouse, and the line indicates the mean ± the standard error of the mean (C) or the median (D). The horizontal dotted line denotes the limit of detection for the assay (n = 6 to 8/group pooled from two experiments).

Mentions: To further investigate the functionality of these delayed antibody responses, we assessed whether these responses could expand after a boosting immunization. C57BL/6 mice were immunized i.m. with 1010 vp of Ad26-SIV Env and depleted of CD4+ T cells on day −1 or left untreated as a control (Fig. 3A). Four months after the primary immunization, mice were boosted i.m. with 1010 vp of Ad5-SIV Env (Fig. 3A). One month after the boosting immunization, the anti-CD4 antibody-treated and untreated mice had equivalent median SIV Env-specific endpoint titers (Fig. 3B), which reflected equivalent mean fold expansions of 54-fold and 43-fold, respectively (P = 0.8) (Fig. 3C). As a final measure of functional capacity, we assessed the ability of these delayed antibodies to neutralize an SIV Env-expressing pseudovirus. No SIV-specific neutralizing antibodies in anti-CD4-treated mice were detected at 1 month postimmunization (Fig. 3D), which is consistent with the lack of Env-specific binding antibodies at this time point (Fig. 1B). However, by 4 months postimmunization, anti-CD4-treated mice had median neutralizing antibody titers that were not significantly different from those in undepleted vaccinated mice (P = 0.9) (Fig. 3D). In both groups, neutralizing antibody titers increased following the boosting immunization, and again, no differences between the two groups were observed (Fig. 3D). Collectively, these data demonstrate that the delayed antibody responses that developed following depletion of CD4+ T cells at the time of primary Ad vector immunization have no detectable defects in boosting capacity, the ability to acquire functional neutralization capacity, isotype proportions, or antigen-binding avidity.


Transient CD4+ T Cell Depletion Results in Delayed Development of Functional Vaccine-Elicited Antibody Responses.

Provine NM, Badamchi-Zadeh A, Bricault CA, Penaloza-MacMaster P, Larocca RA, Borducchi EN, Seaman MS, Barouch DH - J. Virol. (2016)

Boosting capacity and functional neutralization capacity of delayed antibody responses that develop following transient CD4+ T cell depletion. (A) C57BL/6 mice were depleted of CD4+ T cells or left untreated, immunized intramuscularly with 1010 vp of Ad26-SIV Env, and boosted 4 months postprime with 1010 vp of Ad5-SIV Env. (B) SIV Env-specific antibody titers prior to and following boosting immunization. (C) Fold change in SIV Env-specific antibody responses pre- to postboost. (D) Serum 50% neutralization capacity (IC50) of tier 1A SIVmac251.TCLA.15 Env-expressing pseudoviruses or a MuLV negative-control pseudovirus. Each dot represents an individual mouse, and the line indicates the mean ± the standard error of the mean (C) or the median (D). The horizontal dotted line denotes the limit of detection for the assay (n = 6 to 8/group pooled from two experiments).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Boosting capacity and functional neutralization capacity of delayed antibody responses that develop following transient CD4+ T cell depletion. (A) C57BL/6 mice were depleted of CD4+ T cells or left untreated, immunized intramuscularly with 1010 vp of Ad26-SIV Env, and boosted 4 months postprime with 1010 vp of Ad5-SIV Env. (B) SIV Env-specific antibody titers prior to and following boosting immunization. (C) Fold change in SIV Env-specific antibody responses pre- to postboost. (D) Serum 50% neutralization capacity (IC50) of tier 1A SIVmac251.TCLA.15 Env-expressing pseudoviruses or a MuLV negative-control pseudovirus. Each dot represents an individual mouse, and the line indicates the mean ± the standard error of the mean (C) or the median (D). The horizontal dotted line denotes the limit of detection for the assay (n = 6 to 8/group pooled from two experiments).
Mentions: To further investigate the functionality of these delayed antibody responses, we assessed whether these responses could expand after a boosting immunization. C57BL/6 mice were immunized i.m. with 1010 vp of Ad26-SIV Env and depleted of CD4+ T cells on day −1 or left untreated as a control (Fig. 3A). Four months after the primary immunization, mice were boosted i.m. with 1010 vp of Ad5-SIV Env (Fig. 3A). One month after the boosting immunization, the anti-CD4 antibody-treated and untreated mice had equivalent median SIV Env-specific endpoint titers (Fig. 3B), which reflected equivalent mean fold expansions of 54-fold and 43-fold, respectively (P = 0.8) (Fig. 3C). As a final measure of functional capacity, we assessed the ability of these delayed antibodies to neutralize an SIV Env-expressing pseudovirus. No SIV-specific neutralizing antibodies in anti-CD4-treated mice were detected at 1 month postimmunization (Fig. 3D), which is consistent with the lack of Env-specific binding antibodies at this time point (Fig. 1B). However, by 4 months postimmunization, anti-CD4-treated mice had median neutralizing antibody titers that were not significantly different from those in undepleted vaccinated mice (P = 0.9) (Fig. 3D). In both groups, neutralizing antibody titers increased following the boosting immunization, and again, no differences between the two groups were observed (Fig. 3D). Collectively, these data demonstrate that the delayed antibody responses that developed following depletion of CD4+ T cells at the time of primary Ad vector immunization have no detectable defects in boosting capacity, the ability to acquire functional neutralization capacity, isotype proportions, or antigen-binding avidity.

Bottom Line: Upon CD4(+)T cell recovery, transgene-specific serum IgG antibody titers develop and reach a concentration equivalent to that in undepleted control animals.The paradigm is that helper signals must be provided immediately upon antigen exposure, and their absence results in tolerance against the antigen.These data demonstrate that the time when CD4(+)T cell help signals must be provided is more dynamic and flexible than previously appreciated.

View Article: PubMed Central - PubMed

Affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Show MeSH
Related in: MedlinePlus