The migratory Sirpα+CD8lo dendritic cell subset in the thymus has specialised roles in T regulatory cell induction
AI Proietto, S van Dommelen, A D’Amico, M Lahoud, K Shortman, L Wu
Dendritic cells (DC) are a rare but important cell population in ones immune system. They are efficient antigen presenting cells and play important roles not only in the induction of immune responses against invading foreign pathogens, but also in preventing the damage of one’s own tissues by abnormal immune responses, known as autoimmunity. There are many different types of DC resident within the lymphoid tissues such as the thymus, the spleen and the lymph nodes. Each type has a specialised role in the immune system.
The thymus is the organ where T-cells develop. During this process, some T-cells which may react to one’s own tissues (i.e. auto-reactive), are deleted within the thymus in a process called negative selection. This process ensures that very few auto-reactive T-cells can reach other lymphoid tissues. In addition, the few auto-reactive “escapees” can be controlled by a different type of T-cell called the T regulatory cell (T-reg) through suppression of the growth and activation of escaped auto-reactive T-cells. T-regs also develop within the thymus, although the regulation of their development is not fully understood.
Thymic DC include the CD8loSirpα+ and the CD8hiSirpα- conventional DC (cDC) subtypes. Thymic DC were shown to play important roles in negative selection, because they were able to efficiently present self-antigens via MHC class-II molecules to the developing T-cells, which led to activation and subsequent deletion of auto-reactive T-cells. However, their role in the regulation of T-reg cell development in the thymus was unclear. This study investigated the roles of thymic DC subsets in T-reg cell development. Using MHC class II-/- bone marrow chimeric mice, where thymic DC were no longer able to present self-antigen to developing T-cells, we observed a significant reduction in the numbers of T-reg cells in the thymus as well as an increase in auto-reactive CD4+ T cells (Figure 1A), demonstrating, for the first time, the role of DC in both T-reg induction and negative selection. In addition, using an in vitro assay, we found that it is the CD8loSirpα+ DC subset that demonstrates a superior capacity to induce T-regs (B).
Moreover, we showed that CD8loSirpα+ cDCs represent a cDC subset that migrates into the thymus from the blood. Based on these findings we propose a model whereby thymic CD8loSirpα+ cDCs carry antigens from the periphery to the thymus for T-reg induction and negative selection.
Contribution of thymic DC to T-reg generation in vivo and in vitro. (A) Irradiated wild-type (WT) CD45.1 mice were reconstituted with 5x106 MHC class II-/- BM or WT BM (left panel). The total number of CD4+CD8- thymocytes in the MHC class II-/- BM chimeras was increased compared to controls, suggesting a defect in negative selection. The total number of thymic T-regs in the MHC class II-/- BM chimeras was decreased compared to WT controls demonstrating a role for DC in the induction of Tregs (n=20-24 per group) (right panel). (B) Sorted thymic DC subsets (CD45.1) were co-cultured with sorted CD4+CD25- thymocytes (containing T-reg precursors) from CD45.2 mice for 5 days in the presence of IL-7 (left panel). The T-regs (CD25+Foxp3+) generated were analysed by staining the cells for CD45.2, CD4, CD25 and Foxp3. Data are representative of six experiments (right panel). The Sirpα+ thymic DCs were the most efficient inducers of T-regs.
Identification of novel dendritic cell markers in mouse and man
I Caminschi, M Lahoud, K Shortman
Dendritic cells (DC) play a central role in directing immune responses and are therefore ideal targets for immunotherapy. We have identified two novel C-type lectin proteins, Clec9A and Clec12A, that may serve as DC surface targets. They both have selective expression on particular mouse DC subpopulations. Both molecules have a human homologue and we have generated monoclonal antibodies against the mouse and human proteins. Since the translation of mouse DC-biology has, in part, been hampered by the lack of species-conserved markers, Clec9A and Clec12A will allow us to investigate mouse DC-biology and more readily apply this to human DC subsets.
Premature dendritic cell activation impairs immunity
LJ Young, NS Wilson, P Schnorrer, A Mount, GT Belz, WR Heath, JA Villadangos in collaboration with RJ Lundie, BS Crabb (Infection and Immunity Division), NL LaGruta (University of Melbourne) Pub ref: 155, 161, 219
When dendritic cells (DC) encounter pathogen products or vaccine adjuvants, they mature and present antigens associated with the pathogens or the vaccine. We have now found that if DC mature too early, they stop presenting new antigens, including viral antigens synthesised by the DC themselves. Indeed, systemic DC activation caused by injection of pathogen-mimics impaired immunity against subsequently encountered antigens. This impairment could be reversed injecting DC exogenously loaded with antigens. These observations have important implications for the design of prophylactic and therapeutic DC vaccines and contribute to understand the mechanisms causing immunosuppression during systemic blood infections.
The interplay of dendritic cell populations coordinate protective immune responses in pathogen infections
AM Mount, F Masson, P Iliades, S Bedoui, F Kupresanin, WR Heath, GT Belz in collaboration with FR Carbone (University of Melbourne)
Dendritic cells (DC) in the lung detect pathogens and migrate to the lymph nodes to present pathogen antigens to T cells. These lung-derived DC play a critical role in transporting antigenic cargo to other DC that spend their entire lives in the lymph node. These lymph node resistant CD8α DC play a pivotal role in driving the amplification of T cells. In our studies, we have found that after lung infection, both naïve and memory CD8+ “killer” T cells responded to viral antigens presented by CD8α DC, while naïve cells predominantly responded to antigens presented by lung-derived DC. This division of labour between different DC populations provides a mechanism for priming naïve T cell responses in the face of robust T cell memory.