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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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Transient depletion of CD4+ T cells at priming does not alter the isotype distribution or the antigen-binding avidity of delayed antibody (Ab) responses. C57BL/6 mice were depleted of CD4+ T cells or left untreated and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (A and B) Concentrations of serum SIV Env-specific IgG2a (A) and IgG1 (B). (C) Ratios of SIV Env-specific IgG2a to IgG1 serum antibody titers. The horizontal dotted line denotes a ratio of 1. (D) Avidity of SIV Env-specific serum antibodies as determined by a urea disruption assay. Each dot represents an individual mouse, and the medians are indicated by the line (n = 5 to 8/group pooled from two experiments).
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Figure 2: Transient depletion of CD4+ T cells at priming does not alter the isotype distribution or the antigen-binding avidity of delayed antibody (Ab) responses. C57BL/6 mice were depleted of CD4+ T cells or left untreated and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (A and B) Concentrations of serum SIV Env-specific IgG2a (A) and IgG1 (B). (C) Ratios of SIV Env-specific IgG2a to IgG1 serum antibody titers. The horizontal dotted line denotes a ratio of 1. (D) Avidity of SIV Env-specific serum antibodies as determined by a urea disruption assay. Each dot represents an individual mouse, and the medians are indicated by the line (n = 5 to 8/group pooled from two experiments).

Mentions: We sought to determine whether the delayed antibody responses observed after day 60 in mice depleted of CD4+ T cells prior to immunization are functionally normal. We first assessed if the delayed antibody responses exhibited alterations in their isotype proportions. The concentration of IgG2a isotype Env-specific antibodies increased from days 30 to 90 postimmunization in anti-CD4-treated mice, and by day 90, only a statistical trend for differences in antibody concentrations in anti-CD4-treated versus untreated mice was observed (P = 0.06) (Fig. 2A). Similarly, IgG1 isotype Env-specific antibody concentrations increased in anti-CD4-treated mice between days 30 and 90 and reached antibody concentrations equivalent to those in untreated control mice by day 60 (untreated median of 1,924 ng/ml and anti-CD4 median of 1,543 ng/ml; P = 0.2) (Fig. 2B). On both days 60 and 90 postimmunization, the ratio of IgG2a to IgG1 isotype antibodies was equivalent between the anti-CD4-treated and untreated groups (P = 0.3) (Fig. 2C). Finally, we sought to determine if the delayed antibody response that developed following the depletion of CD4+ T cells would have reduced antigen-binding avidity, as measured by using a urea disruption assay (28). Env-specific antibodies in anti-CD4-treated and untreated mice on day 60 or 90 postimmunization displayed no significant differences in Env-binding avidity as determined by urea disruption ELISAs (Fig. 2D). Thus, the delayed antibody responses exhibited no significant abnormalities in their isotypes or binding avidities.


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)

Transient depletion of CD4+ T cells at priming does not alter the isotype distribution or the antigen-binding avidity of delayed antibody (Ab) responses. C57BL/6 mice were depleted of CD4+ T cells or left untreated and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (A and B) Concentrations of serum SIV Env-specific IgG2a (A) and IgG1 (B). (C) Ratios of SIV Env-specific IgG2a to IgG1 serum antibody titers. The horizontal dotted line denotes a ratio of 1. (D) Avidity of SIV Env-specific serum antibodies as determined by a urea disruption assay. Each dot represents an individual mouse, and the medians are indicated by the line (n = 5 to 8/group pooled from two experiments).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836333&req=5

Figure 2: Transient depletion of CD4+ T cells at priming does not alter the isotype distribution or the antigen-binding avidity of delayed antibody (Ab) responses. C57BL/6 mice were depleted of CD4+ T cells or left untreated and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (A and B) Concentrations of serum SIV Env-specific IgG2a (A) and IgG1 (B). (C) Ratios of SIV Env-specific IgG2a to IgG1 serum antibody titers. The horizontal dotted line denotes a ratio of 1. (D) Avidity of SIV Env-specific serum antibodies as determined by a urea disruption assay. Each dot represents an individual mouse, and the medians are indicated by the line (n = 5 to 8/group pooled from two experiments).
Mentions: We sought to determine whether the delayed antibody responses observed after day 60 in mice depleted of CD4+ T cells prior to immunization are functionally normal. We first assessed if the delayed antibody responses exhibited alterations in their isotype proportions. The concentration of IgG2a isotype Env-specific antibodies increased from days 30 to 90 postimmunization in anti-CD4-treated mice, and by day 90, only a statistical trend for differences in antibody concentrations in anti-CD4-treated versus untreated mice was observed (P = 0.06) (Fig. 2A). Similarly, IgG1 isotype Env-specific antibody concentrations increased in anti-CD4-treated mice between days 30 and 90 and reached antibody concentrations equivalent to those in untreated control mice by day 60 (untreated median of 1,924 ng/ml and anti-CD4 median of 1,543 ng/ml; P = 0.2) (Fig. 2B). On both days 60 and 90 postimmunization, the ratio of IgG2a to IgG1 isotype antibodies was equivalent between the anti-CD4-treated and untreated groups (P = 0.3) (Fig. 2C). Finally, we sought to determine if the delayed antibody response that developed following the depletion of CD4+ T cells would have reduced antigen-binding avidity, as measured by using a urea disruption assay (28). Env-specific antibodies in anti-CD4-treated and untreated mice on day 60 or 90 postimmunization displayed no significant differences in Env-binding avidity as determined by urea disruption ELISAs (Fig. 2D). Thus, the delayed antibody responses exhibited no significant abnormalities in their isotypes or binding avidities.

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