Vaccination and immunological memory

Human subjects maintain long-term immunological memory against infective organisms but the mechanism is unclear. CD4+ T helper memory cells (Thmem) are pivotal in controlling humoral and cellular responses, therefore their longevity and response to vaccination are critical for maintenance of protective immunity. To probe the dynamics of the Thmem response to antigenic challenge, we investigated subjects following a booster injection with tetanus toxoid (TT). Expansion of TT-specific Thmem cells, and cytokine production, showed complex kinetics. Strikingly, parallel expansion and cytokine production occurred in pre-existing Thmem cells specific for two other common antigens, Purified Protein Derivative of tuberculin (PPD), and Candida albicans (C.alb). Bystander expansion occurred in Thmem but not in Thnaive cells. Antibody production against TT peaked ~2 weeks post-vaccination and gradually declined. However, pre-existing antibody against the other antigens did not change. It appears that, although all Thmem cells are readily stimulated to expand, antibody responses are controlled by antigen availability. These human findings which relate to the maintenance of memory and have consequences for assessments of specific T-cell responses to vaccination, have been further investigated in a mouse model. A transgenic model (OT-II) where CD4+ T cells express a TCR specific for an ovalbumin peptide (peptide 323-339, OVAp) was used first to ask the question as to whether naïve or antigen-activated T cells were influenced in a bystander manner during a secondary immune response directed against a protein antigen that was unrelated to their cognate one. For this, carboxyfluorescein diacetate succunimidyl ester (CFSE)-labeled OT-II cells were adoptively transferred, either as naïve or 4 following in vitro activation with OVAp, into C57/BL6 wild type recipient mice which were immune to TT. Recipient mice were then challenged with TT antigen and susceptibility of OT-II cells to bystander activation and proliferation was tested. Naïve T cells were found not to be influenced, but antigen-activated cells were responsive and underwent further activation and bystander proliferation, with accompanying phenotypic changes. Interestingly bystander proliferation appeared to be proportional to the strength of TT-specific cellular immune response. The second question was whether the bystander influence on activated T cells was also evident during a primary immune response to TT. To address this question, antigen-activated OT-II cells and control naïve cells were adoptively transferred into wild type naïve recipient mice and their activation and proliferation was assessed after challenge with TT. In this case no bystander activation or proliferation of OT-II cells was observed. These results underline the susceptibility to bystander activation and proliferation as a unique feature of antigen-activated OT-II cells as opposed to naïve OT-II cells. They mirror those obtained in our study on human subjects and add formal proof of bystander proliferation occurring in vivo. Furthermore this well defined mouse model paves the way for further investigations aimed at addressing the mechanisms responsible for the observed phenomenon.

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Southampton

Year dc:date.issued

2008

Author dc:creator

• Di Genova, Gianfranco

Advisor dc:contributor.advisor

• Stevenson, Freda