Several areas of immunological research promise to have a major impact. The generation of new vaccines that are both safe and effective remains a goal of enormous practical and societal significance. HIV infection, drug-resistant tuberculosis, and malaria are three examples of major killers, each responsible for millions of deaths annually, for which no effective vaccines are currently available. Research must incorporate cell biological as well as immunological concepts to solve this unmet need. Even though some of the most successful vaccines were developed in the absence of detailed immunological knowledge, the current regulatory climate demands a more detailed understanding of the composition of a successful vaccine and why it works.

Lymphocytes are among the few cell types that can be studied as primary cells that continue to perform cell- and tissue-type-specific behavior in tissue culture. This trait makes lymphocytes an attractive model in which to study details of signal transduction, to explore interactions between well-defined, different cell types under defined laboratory conditions, and to accurately measure and model the responses evoked by specific stimuli.

The ability of lymphocytes to create antigen-specific receptors of nearly limitless variability comes at a price: the generation of self-reactive receptors, which is the major contributing factor to autoimmune diseases (e.g., type I diabetes, multiple sclerosis, and arthritis). Vertebrates have several mechanisms for keeping such self-reactive lymphocytes in check, but none of them is foolproof. We must understand how tolerance for self antigens is generated, maintained, and ultimately broken at the onset of autoimmune disease. This understanding should help define new strategies for manipulating and controlling self-reactive lymphocytes to prevent or treat autoimmune diseases.

With advances in our understanding of stem cells and how they can be used in the treatment of diseases (e.g., Parkinson’s disease, muscular dystrophy, and spinal cord injuries), transplantation of heterologous stem cells (i.e., derived from an individual other than the patient) is one of several options. The immune system’s ability to recognize as foreign such transplanted stem-cell derivatives is a factor that will limit the use of heterologous stem cells. Consequently, new means to suppress responses to these transplants, or to induce tolerance for them, are important goals.

More refined genetic tools continue to allow identification of additional lymphocyte subsets, often with distinct functions. Improved classification schemes will help us to understand lymphocyte function and so open the door to selective manipulation of lymphocyte function for therapeutic gain.

Our understanding of the interplay between innate and adaptive immune responses, and of the many ways in which pathogens interfere with both innate and adaptive immunity, will benefit from our increased understanding of the genome sequences and genome structures of both host and pathogen. The use of genetically modified pathogenic organisms as probes for host immune function is a rapidly expanding area of basic cell biological research.