Transient CD4+ T Cell Depletion Results in Delayed Development of Functional Vaccine-Elicited 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.
Affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.Show MeSH
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Mentions: We first sought to determine the time at which CD4+ T cell help is required for the induction of transgene antigen-specific antibody responses by Ad vector vaccination. To accomplish this, C57BL/6 mice were immunized i.m. with 1010 vp of Ad26-SIV Env and depleted of CD4+ T cells by the administration of anti-CD4 antibody GK1.5 on either day −1, day 3, day 7, day 10, day 14, day 21, or day 28 postimmunization or left untreated, as a control (Fig. 1A). In untreated control mice, robust SIV Env-specific serum antibody titers were detected on day 14 postimmunization and were maintained for at least 90 days (Fig. 1B). Depletion of CD4+ T cells prior to immunization or on day 3 postimmunization resulted in nearly undetectable Env-specific antibody responses at days 14 and 30 postimmunization (Fig. 1B). Depletion of CD4+ T cells on day 7 or 10 postimmunization had progressively less of an impact on Env-specific antibody titers measured on day 30, and depletion of CD4+ T cells on or after day 14 postimmunization had no impact on antibody titers measured on day 30 (Fig. 1B). As expected, the decrease in antibody titers observed following the depletion of CD4+ T cells was highly correlated with reductions in the frequencies of germinal center B cells in the iliac (draining) lymph nodes (LNs) on day 14 postimmunization (r = 0.76 by Spearman test; P = 0.001) (Fig. 1C to E). Signaling by CD4+ T cells through CD40 is a well-described mechanism by which CD4+ T cells promote antibody responses (13). We confirmed that CD40 was an important signaling pathway for antigen-specific antibody responses following Ad vector immunization, as the absence of CD40L or CD40 resulted in a complete abolishment of Env-specific antibody responses on day 30 postimmunization (Fig. 1F). Thus, following Ad vector immunization, induction of antigen-specific antibody responses requires CD4+ T cell help to promote germinal center responses via CD40-derived signals, consistent with data obtained by using other experimental systems (34).
Affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.