Research Highlights
Claire Chougnet, who directs a research program aimed at understanding the molecular mechanisms that underlie T cell dysfunction in aging (and in HIV / AIDS), has developed a new program of research aimed at understanding the development of T cell responses in early life. The ontogeny of immune responses in human neonates is not well understood, in part because T cell development in fetal life is divergent in humans and the experimental systems used most often by immunologists − inbred mice. Importantly, descriptive human studies and experimental studies in sheep have suggested that uncontrolled T cell responses are important in the development of bronchopulmonary dysplasia, which develops in about 25 percent of low-birth weight preterm infants. In collaboration with Alan Jobe and Suhas Kallapur from Neonatal Institute, Chougnet has set up novel, extramurally funded, complementary studies of T cell ontogeny in premature infants, sheep and non-human primates.
In a collaborative effort between Edith Janssen (Molecular Immunology) and Jonathan Katz (Endocrinology; adjunct faculty in Molecular Immunology) significant strides have been made in the identification and characterization of a specific dendritic cell population that orchestrates immune responses to self. Harnessing these dendritic cells for autologous cancer vaccine treatments significantly increases the efficacy of anti-tumor treatment in tumor-bearing mice. On the other hand, dysregulation of this dendritic cell population was found to be a major factor in breaking of peripheral tolerance and induction of the autoimmune disease type 1 diabetes in diabetes-prone NOD mice. Their two papers in press in The Journal of Immunology illustrate the broad implications and therapeutic potential of their observations and exemplify how melding two separate fields can unexpectedly accelerate the understanding of basic immunological principles and open new avenues for therapeutic approaches.
Kasper Hoebe recently identified an “endogenous adjuvant” pathway mediated by NK cells. NK cells detect and kill pathogen-infected host cells, as well as neoplastic cells and tissue allografts. However, studies from the Hoebe laboratory have shown that they discharge another duty as well: one that establishes a strong tie between NK cells and the adaptive immune system. Of key importance in this pathway is the recognition and killing of antigen expressing target cells by NK cells. Subsequently, NK cell-induced cell death is recognized by DCs, leading to antigen cross-presentation and to strong cellular and humoral immune responses. Hoebe’s laboratory aims to exploit the knowledge obtained on NK cell-driven adaptive immune responses for the generation of novel vaccines for chronic infectious diseases such HIV / AIDS, as well as for cancer vaccine development.
With the prevalence, morbidity and mortality of allergic asthma continuing its dramatic rise in the Westernized world, it is clear that new therapies are needed. The rational development of novel therapeutic approaches will likely depend upon a better molecular understanding of pathogenesis. Allergic asthma is thought to arise from maladaptive, Th2-polarized immune responses to ubiquitous, otherwise innocuous environmental proteins. While the proteins so targeted represent a tiny fraction of the airborne proteins humans are exposed to, allergenicity is a quite public phenomenon − the same proteins typically behave as aeroallergens across the human population. Why particular proteins tend to act as allergens in susceptible hosts is a fundamental mechanistic question that has remained largely unclear. The major house dust mite allergen, Der p 2, has structural homology with MD-2, the lipopolysaccharide (LPS)-binding component of the TLR4 signaling complex. Data from the Karp lab have shown that: (a) Der p 2 has functional homology with MD-2 as well, facilitating signaling through direct interactions with the TLR4 complex, and reconstituting LPS-driven TLR4 signaling in the absence of MD-2; (b) Der p 2 facilitates LPS signaling in primary antigen presenting cells, with or without MD-2 being present; and (c) the in vivo allergenic activity of Der p 2 mirrors its in vitro functional and biochemical activity: Der p 2 efficiently drives airway Th2 inflammation in vivo in a TLR4-dependent manner, retaining this ability in the absence of MD-2. These data suggest that Der p 2 tends to be targeted by adaptive immune responses because of its auto-adjuvant properties. The fact that other members of the MD-2 lipid-binding domain family are major allergens and, more broadly, that more than 50 percent of defined major allergens are lipid-binding proteins, suggests that intrinsic adjuvant activity by such proteins and their accompanying lipid cargo is likely to have some generality as a mechanism underlying the phenomenon of allergenicity.
