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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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Related in: MedlinePlus

Germinal center B cell responses develop following transient depletion of CD4+ T cells. C57BL/6 mice were depleted of CD4 T cells a single time (anti-CD4 at prime) (red circles), depleted of CD4 T cells repeatedly (anti-CD4 repeated) (blue circles), or left untreated (gray circles) and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (A to C) Representative flow cytometry plots (A), group average percentages (B), and absolute numbers (C) of germinal center B cells in the iliac (draining) LNs on day 60 postimmunization. (D) Expression of IgM and IgD on germinal center B cells on day 60 postimmunization. Each dot represents an individual mouse, and the means ± standard errors of the means are indicated by a line (n = 15/group pooled from three experiments).
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Figure 5: Germinal center B cell responses develop following transient depletion of CD4+ T cells. C57BL/6 mice were depleted of CD4 T cells a single time (anti-CD4 at prime) (red circles), depleted of CD4 T cells repeatedly (anti-CD4 repeated) (blue circles), or left untreated (gray circles) and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (A to C) Representative flow cytometry plots (A), group average percentages (B), and absolute numbers (C) of germinal center B cells in the iliac (draining) LNs on day 60 postimmunization. (D) Expression of IgM and IgD on germinal center B cells on day 60 postimmunization. Each dot represents an individual mouse, and the means ± standard errors of the means are indicated by a line (n = 15/group pooled from three experiments).

Mentions: As CD4+ T cells were critical for promoting the formation of germinal center responses following Ad vector immunization (Fig. 1), we hypothesized that when CD4+ T cells recovered following transient depletion, de novo germinal center responses would be induced. On day 30 postimmunization, no germinal center B cells were detected in the iliac lymph nodes of Ad26-SIV Env-immunized mice treated with anti-CD4 antibody at priming (Fig. 5A). However, by day 60 postimmunization, when the frequency of CD4+ T cells had returned to near-basal levels in these animals, robust germinal center responses were observed. These responses were equivalent in frequency and absolute number of cells to the germinal center responses measured in untreated control mice (Fig. 5A to C). These germinal center B cells also displayed normal downregulation of IgM and IgD (Fig. 5D). Recovery of CD4+ T cells was required for the induction of these delayed germinal center responses, as sustained depletion of CD4+ T cells prevented germinal centers from developing (Fig. 5A to C). Thus, recovery of CD4+ T cells results in the generation and expansion of germinal centers and the development of the delayed antibody response.


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)

Germinal center B cell responses develop following transient depletion of CD4+ T cells. C57BL/6 mice were depleted of CD4 T cells a single time (anti-CD4 at prime) (red circles), depleted of CD4 T cells repeatedly (anti-CD4 repeated) (blue circles), or left untreated (gray circles) and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (A to C) Representative flow cytometry plots (A), group average percentages (B), and absolute numbers (C) of germinal center B cells in the iliac (draining) LNs on day 60 postimmunization. (D) Expression of IgM and IgD on germinal center B cells on day 60 postimmunization. Each dot represents an individual mouse, and the means ± standard errors of the means are indicated by a line (n = 15/group pooled from three experiments).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Germinal center B cell responses develop following transient depletion of CD4+ T cells. C57BL/6 mice were depleted of CD4 T cells a single time (anti-CD4 at prime) (red circles), depleted of CD4 T cells repeatedly (anti-CD4 repeated) (blue circles), or left untreated (gray circles) and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (A to C) Representative flow cytometry plots (A), group average percentages (B), and absolute numbers (C) of germinal center B cells in the iliac (draining) LNs on day 60 postimmunization. (D) Expression of IgM and IgD on germinal center B cells on day 60 postimmunization. Each dot represents an individual mouse, and the means ± standard errors of the means are indicated by a line (n = 15/group pooled from three experiments).
Mentions: As CD4+ T cells were critical for promoting the formation of germinal center responses following Ad vector immunization (Fig. 1), we hypothesized that when CD4+ T cells recovered following transient depletion, de novo germinal center responses would be induced. On day 30 postimmunization, no germinal center B cells were detected in the iliac lymph nodes of Ad26-SIV Env-immunized mice treated with anti-CD4 antibody at priming (Fig. 5A). However, by day 60 postimmunization, when the frequency of CD4+ T cells had returned to near-basal levels in these animals, robust germinal center responses were observed. These responses were equivalent in frequency and absolute number of cells to the germinal center responses measured in untreated control mice (Fig. 5A to C). These germinal center B cells also displayed normal downregulation of IgM and IgD (Fig. 5D). Recovery of CD4+ T cells was required for the induction of these delayed germinal center responses, as sustained depletion of CD4+ T cells prevented germinal centers from developing (Fig. 5A to C). Thus, recovery of CD4+ T cells results in the generation and expansion of germinal centers and the development of the delayed antibody response.

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