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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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Repeated depletion of CD4+ T cells prevents development of delayed antibody responses. (A) C57BL/6 mice were depleted of CD4+ T cells a single time (anti-CD4 at prime), depleted of CD4+ T cells repeatedly (anti-CD4 repeated), or left untreated and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (B) Frequency of CD4 T cells in iliac (draining) LNs. (C) SIV Env-specific serum-binding antibody titers. (D) Serum SIV Env-specific antibody titers on day 60 postimmunization from wild-type or MHC-II KO mice immunized with 1010 vp of Ad26-SIV Env. (E) Serum SIV Env-specific antibody titers on day 60 postimmunization from mice that underwent adult thymectomy, or not, and were treated with anti-CD4 antibody, or not, as indicated. Each dot represents an individual mouse, and the line indicates the mean ± the standard error of the mean (B) or median (C to E). The horizontal dotted line denotes the limit of detection (LOD) for the assay (for panel B, n = 5/group from one experiment [day 30] or n = 20/group pooled from four experiments [day 60]; for panel C, n = 10/group pooled from two experiments [day 30] or n = 20/group pooled from four experiments [day 60]; for panel D, n = 8/group pooled from two experiments; for panel E, n = 10/group pooled from two experiments).
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Figure 4: Repeated depletion of CD4+ T cells prevents development of delayed antibody responses. (A) C57BL/6 mice were depleted of CD4+ T cells a single time (anti-CD4 at prime), depleted of CD4+ T cells repeatedly (anti-CD4 repeated), or left untreated and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (B) Frequency of CD4 T cells in iliac (draining) LNs. (C) SIV Env-specific serum-binding antibody titers. (D) Serum SIV Env-specific antibody titers on day 60 postimmunization from wild-type or MHC-II KO mice immunized with 1010 vp of Ad26-SIV Env. (E) Serum SIV Env-specific antibody titers on day 60 postimmunization from mice that underwent adult thymectomy, or not, and were treated with anti-CD4 antibody, or not, as indicated. Each dot represents an individual mouse, and the line indicates the mean ± the standard error of the mean (B) or median (C to E). The horizontal dotted line denotes the limit of detection (LOD) for the assay (for panel B, n = 5/group from one experiment [day 30] or n = 20/group pooled from four experiments [day 60]; for panel C, n = 10/group pooled from two experiments [day 30] or n = 20/group pooled from four experiments [day 60]; for panel D, n = 8/group pooled from two experiments; for panel E, n = 10/group pooled from two experiments).

Mentions: We hypothesized that the development of delayed antibody responses following CD4+ T cell depletion reflected the transient nature of CD4+ T cell depletion following a single regimen of anti-CD4 antibody treatment. To test this, C57BL/6 mice were immunized i.m. with 1010 vp of Ad26-SIV Env and divided into three experimental groups: (i) mice treated with anti-CD4 antibody on day −1 (anti-CD4 at prime), (ii) mice treated with anti-CD4 antibody on day −1 and again every 14 to 21 days (anti-CD4 repeated), and (iii) untreated controls (Fig. 4A). Administration of anti-CD4 antibody at prime resulted in the complete depletion of CD4+ T cells for at least 30 days, but the CD4+ T cell population had largely recovered by day 60 (Fig. 4B). The recovery of the CD4+ T cell compartment coincided with the development of SIV Env-specific antibody responses (r = 0.68 by Spearman test; P = 0.0009) (data not shown and Fig. 4C). In contrast, repeated administration of anti-CD4 antibody maintained the depletion of CD4+ T cells for at least 60 days (Fig. 4B). The repeated administration of anti-CD4 antibody prevented the development of SIV Env-specific antibody responses in 18 of 20 mice by day 60 postimmunization (P < 0.001) (Fig. 4C). Consistent with the observation that repeated administration of anti-CD4 antibody prevented the development of a delayed antibody response, MHC-II KO mice, which permanently lack CD4+ T cells, had no SIV Env-specific antibody responses on day 60 postimmunization (Fig. 4D). Thus, the recovery of CD4+ T cells following anti-CD4 antibody treatment is necessary for the development of these delayed antibody responses.


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)

Repeated depletion of CD4+ T cells prevents development of delayed antibody responses. (A) C57BL/6 mice were depleted of CD4+ T cells a single time (anti-CD4 at prime), depleted of CD4+ T cells repeatedly (anti-CD4 repeated), or left untreated and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (B) Frequency of CD4 T cells in iliac (draining) LNs. (C) SIV Env-specific serum-binding antibody titers. (D) Serum SIV Env-specific antibody titers on day 60 postimmunization from wild-type or MHC-II KO mice immunized with 1010 vp of Ad26-SIV Env. (E) Serum SIV Env-specific antibody titers on day 60 postimmunization from mice that underwent adult thymectomy, or not, and were treated with anti-CD4 antibody, or not, as indicated. Each dot represents an individual mouse, and the line indicates the mean ± the standard error of the mean (B) or median (C to E). The horizontal dotted line denotes the limit of detection (LOD) for the assay (for panel B, n = 5/group from one experiment [day 30] or n = 20/group pooled from four experiments [day 60]; for panel C, n = 10/group pooled from two experiments [day 30] or n = 20/group pooled from four experiments [day 60]; for panel D, n = 8/group pooled from two experiments; for panel E, n = 10/group pooled from two experiments).
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Figure 4: Repeated depletion of CD4+ T cells prevents development of delayed antibody responses. (A) C57BL/6 mice were depleted of CD4+ T cells a single time (anti-CD4 at prime), depleted of CD4+ T cells repeatedly (anti-CD4 repeated), or left untreated and immunized intramuscularly with 1010 vp of Ad26-SIV Env. (B) Frequency of CD4 T cells in iliac (draining) LNs. (C) SIV Env-specific serum-binding antibody titers. (D) Serum SIV Env-specific antibody titers on day 60 postimmunization from wild-type or MHC-II KO mice immunized with 1010 vp of Ad26-SIV Env. (E) Serum SIV Env-specific antibody titers on day 60 postimmunization from mice that underwent adult thymectomy, or not, and were treated with anti-CD4 antibody, or not, as indicated. Each dot represents an individual mouse, and the line indicates the mean ± the standard error of the mean (B) or median (C to E). The horizontal dotted line denotes the limit of detection (LOD) for the assay (for panel B, n = 5/group from one experiment [day 30] or n = 20/group pooled from four experiments [day 60]; for panel C, n = 10/group pooled from two experiments [day 30] or n = 20/group pooled from four experiments [day 60]; for panel D, n = 8/group pooled from two experiments; for panel E, n = 10/group pooled from two experiments).
Mentions: We hypothesized that the development of delayed antibody responses following CD4+ T cell depletion reflected the transient nature of CD4+ T cell depletion following a single regimen of anti-CD4 antibody treatment. To test this, C57BL/6 mice were immunized i.m. with 1010 vp of Ad26-SIV Env and divided into three experimental groups: (i) mice treated with anti-CD4 antibody on day −1 (anti-CD4 at prime), (ii) mice treated with anti-CD4 antibody on day −1 and again every 14 to 21 days (anti-CD4 repeated), and (iii) untreated controls (Fig. 4A). Administration of anti-CD4 antibody at prime resulted in the complete depletion of CD4+ T cells for at least 30 days, but the CD4+ T cell population had largely recovered by day 60 (Fig. 4B). The recovery of the CD4+ T cell compartment coincided with the development of SIV Env-specific antibody responses (r = 0.68 by Spearman test; P = 0.0009) (data not shown and Fig. 4C). In contrast, repeated administration of anti-CD4 antibody maintained the depletion of CD4+ T cells for at least 60 days (Fig. 4B). The repeated administration of anti-CD4 antibody prevented the development of SIV Env-specific antibody responses in 18 of 20 mice by day 60 postimmunization (P < 0.001) (Fig. 4C). Consistent with the observation that repeated administration of anti-CD4 antibody prevented the development of a delayed antibody response, MHC-II KO mice, which permanently lack CD4+ T cells, had no SIV Env-specific antibody responses on day 60 postimmunization (Fig. 4D). Thus, the recovery of CD4+ T cells following anti-CD4 antibody treatment is necessary for the development of these delayed antibody responses.

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