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Nussenzweig’s laboratory studies the molecular aspects of the immune system’s innate and adaptive responses using a combination of biochemistry, molecular biology, and genetics. For work on adaptive immunity, he focuses on B lymphocytes and antibodies to HIV-1, while his studies of innate immunity focus on dendritic cells.

The immune system protects vertebrates from a multitude of pathogens. Two types of immune responses have evolved to accomplish this task: one innate and the other adaptive. Lymphocytes are the primary effectors of adaptive immunity and assemble a diverse repertoire of immune receptors using a somatic gene recombination process known as V(D)J recombination. This process enables the production of a very large number of unique receptors that recognize almost any antigen, as well as self-reactive receptors, which must be silenced to prevent autoimmune diseases.

The multitude of antigen receptors produced by V(D)J recombination are relatively low-affinity and must be refined by somatic hypermutation and class switch recombination to produce the high-affinity antibodies that protect against most pathogens, including HIV-1. Hypermutation and selection occur in specialized micro-anatomical compartments called germinal centers. Nussenzweig’s laboratory investigates the molecular basis of such hypermutation, and the selection for high affinity antibody-producing cells in the germinal center.

Understanding the rules that govern hypermutation and selection is especially relevant to effective vaccine responses. Nussenzweig’s research aims to understand these processes with the goal of creating vaccines for pathogens such as HIV-1. As part of that effort his laboratory has cloned highly potent human antibodies to HIV-1 that are currently being used in clinical studies of HIV-1 prevention and therapy.

A second area of interest is the physiological function and development of dendritic cells. Current studies focus on outlining the pathway of human dendritic cell development and differentiation.

Nussenzweig’s experiments are consistent with the notion that self-antigens induce tolerance. In contrast, antigens taken up by dendritic cells in the context of activation stimuli, such as those found during inflammation or tissue destruction, induce prolonged T cell activation. This steady-state tolerizing function of dendritic cells may be essential to their role in eliciting immunity. During inflammation or infection, they present self-antigens simultaneously with non-self-antigens. By establishing tolerance to self-antigens before challenge with pathogens, dendritic cells can focus the adaptive immune system entirely on the pathogen, thereby avoiding autoimmunity. The ability to target antigens to dendritic cells and control their function in vivo has significant implications for the development of vaccines and therapies for autoimmunity. Recently, the lab defined distinct progenitor lineages for classical spleen dendritic cells, plasmacytoid dendritic cells, and monocytes, a step toward antigen-specific targeting.