Antigen-specific CD4 1 T cells are central to natural and vaccine-induced immunity. An ongoing antigen-specific T-cell response can, however, influence surrounding T cells with unrelated antigen specificities. We previously observed this bystander effect in healthy human subjects following recall vaccination with tetanus toxoid (TT). Since this interplay could be important for maintenance of memory, we have moved to a mouse model for further analysis. We investigated whether boosting memory CD4 1 T cells against TT in vivo would influence injected CD4 1 TCR transgenic T cells (OT-II) specific for an unrelated OVA peptide. If OT-II cells were pre-activated with OVA peptide in vitro, these cells showed a bystander proliferative response during the ongoing parallel TT-specific response. Bystander proliferation was dependent on boosting of the TT-specific memory response in the recipients, with no effect in naive mice. Bystander stimulation was also proportional to the strength of the TT-specific memory T-cell response. T cells activated in vitro displayed functional receptors for IL-2 and IL-7, suggesting these as potential mediators. This crosstalk between a stimulated CD4 1 memory T-cell response and CD4 1 T cells activated by an unrelated antigen could be important in human subjects continually buffeted by environmental antigens.
Induction of antibody-mediated immunity against hematologic malignancies requires CD4 ؉ T-cell help, but weak tumor antigens generally fail to induce adequate T-cell responses, or to overcome tolerance. Conjugate vaccines can harness alternative help to activate responses, but memory B cells may then be exposed to leaking tumor-derived antigen without CD4 ؉ T-cell support. We showed previously using lymphoma-derived idiotypic antigen that exposure to "helpless" antigen silences the majority of memory IgG ؉ B cells. Transfer experiments now indicate that silencing is permanent. In marked contrast to IgG, most coexisting IgM ؉ memory B cells exposed to "helpless" antigen survive. Confirmation in a hapten (NP) model allowed measurement of affinity, revealing this, rather than isotype, as the determinant of survival. IntroductionTumor antigens are generally weakly immunogenic, and T-cell responses can be subject to tolerogenic pressure. 1 To avoid this, vaccines have been designed as conjugates of tumor antigens with immunogenic molecules, such as KLH. 2 Conjugation captures the large undamaged CD4 ϩ T-cell repertoire, providing T-cell help for the antitumor immune responses. 2,3 Idiotypic (Id) Ig-KLH vaccines aimed to suppress B-cell tumors via an anti-Id response are one example of the promise of this approach. [4][5][6] We have used a similar strategy to deliver Id fusion proteins via DNA vaccines. 7,8 The Id is composed of tumor-derived single chain Fv and is linked to the fragment C (FrC) of tetanus toxin. DNA vaccines encoding Id-FrC fusion proteins induce high levels of anti-Id antibody and protective immunity against B-cell lymphoma. 9 Continuous suppression of lymphoma cell growth probably requires maintenance of antibody levels. Although long-lived plasma cells can secrete antibody for extended periods, 10 memory B cells are also required. Survival factors for memory B cells are unclear, but antigen appears unnecessary. 11,12 For antibody responses induced by conjugate vaccines, the question of the effect of confronting memory B cells with free unconjugated "helpless" antigen, potentially derived from residual or emergent tumor, arises. In the case of Id antigen, or for carbohydrate antigens, this led to dramatic loss of memory B cells. 13 We found previously that the major fraction of the IgG component of the memory B-cell response induced by a DNA Id-FrC fusion vaccine was completely and specifically silenced by Id protein alone. 14 In contrast, Id protein coupled to FrC protein rescued and boosted the anti-Id IgG response, indicating the critical importance of CD4 ϩ T-cell help for maintenance of the memory B-cell response.We have now shown that silencing of the anti-Id IgG response by unconjugated antigen is permanent, but the surprising observation was that the IgM response appeared relatively unscathed. To assess the wider applicability of these findings and to investigate the effects of antigen on memory B cells at different maturational stages, we have used a model antigen, the well-defined hapten...
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