Voie d'immunisation et séquence d'administration de l ... - TEL

tel-00827710, version 1 - 29 May 2013
5) Different T cell activation depending on the timing of activation?
Our immunoscope data (Figures 29 and 30), as well as the work from Van Heijst (van Heijst
et al., 2009), suggest that the route of immunization will not impact T cell recruitment and or
T cell activation because the recruitment occurs rapidly regarless the site of immunization.
However other studies have investigated the timing of T cell recruitment to lymphoid organs
upon immunization and demonstrated that this timing plays a role in the differential activation
of these cells after immunization. Specifically, they compared naïve T cells that are already
present in the draining lymphoid organ at the time of immunization to the “latecomer” T cells
that are recruited later to the lymphoid tissue after immunization. Catron and colleagues
studied CD4 + T cell responses after i.d. immunization of antigen and isolated the lymphoid
resident T cells from the ‘latecomers” using treatment with an anti-CD62L antibody to
prevent latecomer T cell entry into lymph node (Catron et al., 2006). They showed that the
latecomer cells divided less due to a lower density of peptide-MHC-II complexes on DC
surfaces and competition with T cells that already divided and, thus, became central-memory
cells. D’Souza et al. did similar studies for CD8 + T cells after viral infection. They compared
activation and differentiation of low numbers of specific T cells that were transferred at the
time of, or several days after infection. They observed that the timing of recruitment had a
substantial impact on the differentiation program of T cells (D'Souza and Hedrick, 2006).
These studies can be directly compared to the work reported here. Upon i.d. immunization,
antigen cross-presentation remains localized mainly in the skin-draining lymph node. Some
naïve T cells are resident in this lymphoid organ at the time of injection. Other, recirculating
naïve T cells will be attracted via inflammatory signals and will enter this lymph node over
the course of a prolonged period of time, thereby resulting in the non-synchronous activation
of antigen-specific T cells. It is possible that T cells that arrive later may receive less
stimulatory signals and are incompetition with specific T cells that have already divided. This
differential activation based on timing of recruitment and inter-cellular competition for
stimulatory signals may explain the extensive diversity of functional T cells generated after
i.d. immunization. In contrast, i.v. immunization induces a systemic dissemination of antigen
and allows for a more simultaneous activation of antigen-specific T cells, resulting in a
relatively functionally homogenous T cell population.
C. Clinical applications
Our studies strongly highlight the importance of considering the route of immunization and
persistence of antigen presentation in the design of clinical trials and vaccine strategies.
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