Most vaccines against intracellular pathogens aim to induce a population of CD8+ memory T cells of sufficient magnitude, persistence, localization, and function to protect the host from infection. The precise signals required to generate this type of immunity (known as protective immunity) are not well defined, which restricts our ability to design “smart vaccines” that might take advantage of immune mechanisms that can be used to optimize the overall response.
Traditionally, dendritic cells (DCs) have been recognized as the sentinels of the body, carrying antigenic material from distant sites such as the skin to draining lymph nodes, where the cells present antigenic fragments on their major histocompatibility complex molecules to T cells. This allows T cells to screen the body for infection simply by scanning DCs in the many lymph nodes throughout the secondary immune system. This simple paradigm has served us well, but recently we have begun to recognize that there are multiple subsets of DCs, raising the question of how this scheme can accommodate such diversity. In humans, there are two major types of DC, the conventional DCs and the plasmacytoid DCs; the latter appear to play an important role in innate immunity through production of interferon alpha. These two DC types are also present in mice, but murine conventional DCs have been further subdivided into as many as five subtypes.
DCs, together with CD4+ (helper) T cells, coordinate initiation of the immune response. In small-animal models of viral and pathogen (such as malaria and listeria) infection, we have established that CD4+ T cells provide critical signals to DCs that enable them to effectively activate killer T cells. We hypothesized that, in an immune response, DC subsets are specialized and coordinated to ensure that the appropriate response is generated. Surprisingly, during pathogen infections the interactions of CD4+ T cells with a single subset of DCs, those that express the surface marker CD8alpha, appear to be critical in providing the signals necessary to generate effector and memory CD8+ T cells.
Our studies are beginning to explain some of the diversity of the DC subtypes, which relates to their tissue location and migratory properties. Examination of the presentation of viral antigens after lung infection revealed that some diversity could be accounted for by the division of DCs into lymph node–resident versus tissue-derived migratory populations. In particular, we found that, although a CD11b−CD8− DC subtype presented viral antigens after migration from the lung, there was also clear evidence that a CD8+CD205+ DC subset presented viral antigens despite remaining in the lymph node (never having entered the lung). We speculated that the latter subset obtained its antigen from the migratory DCs. Further studies have revealed that DCs are critical for presentation of viral antigens to both naive and memory T cells and provide strong evidence for an interplay between migratory and lymph node–resident DCs in the generation of T cell responses.
One of our specific research interests is to understand how different DC subsets are coordinated during an immune response to generate effector and memory T cells during acutely cleared pathogen infections (influenza virus, Listeria) and persistent infections (herpesvirus, Leishmania). We also wish to investigate the processes by which DCs undergo commitment to differentiation pathways as well as the developmental mechanisms determining effector or memory T cell fate, as dictated by different DC subsets. We are also investigating the cellular mechanisms (magnitude and duration of antigen presentation) that drive expansion, maintenance, and recall of naive and memory T cells and the transcriptional regulation of naive and memory T cell differentiation to generate protective immunity.
An increased understanding of the factors that influence the quality of virus-specific cellular immunity will enable the design of novel vaccine strategies, identify improved vaccine candidates, and better measure the efficacy of such strategies. Moreover, this work has applications in measuring the quality of immunity to some cancers and will help refine treatment of patients undergoing immune reconstitution (after tissue transplants, for example), where immune quality can be tested and monitored.
Last updated October 2008
