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Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
1 Correspondence: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892. E-mail: hrosenberg{at}niaid.nih.gov
This work was selected as a Pivotal Advance because it highlights an extraordinarily interesting and potentially important biological activity of neutrophils that has heretofore gone unexamined. In this work, the authors demonstrate that the functional biology of the neutrophilic leukocyte is altered by the nature of material that is phagocytosed. Specifically, the authors demonstrate surface expression of heterologous MHC class II that has been taken up from the periphery, which enables neutrophils to induce proliferation and cytokine expression in alloreactive T cells.
Dr. Griebel, one of the most fascinating features about this work is that this possibility has really been right in front of our eyes all the time. The observation that neutrophils take up material from the extracellular space was originally made by Eli Metchnikoff—it just took the right eyes and the proverbial "prepared mind" to comprehend the full biologic potential of this activity. Where did this idea come from?
PG: This manuscript and our previous study [1 ] in which we first documented the fact that bovine PMNs could acquire membrane components from other cells was directed primarily by the energies and curiosity of my excellent Ph.D. student, Tyler Whale, who is the first author on both of these publications. Here at Vaccine and Infectious Disease Organization (VIDO) at the University of Saskatchewan, we are focused on vaccine technologies and interactions with the immune system. Tyler noted that bovine adenovirus vectors stimulated mucosal immunity [2 ] and likewise had a particular tropism for neutrophils. As such, he wondered whether there might be some specific conditions under which neutrophils might function as antigen-presenting cells. While there was some literature suggesting that neutrophils might present antigen, in our hands, MHC class II expression on bovine neutrophils was detected only if the neutrophils were co-cultured directly with peripheral blood mononuclear cells (PBMCs). We were not able to detect induction of MHC II mRNA expression in neutrophils, but instead we demonstrated passive acquisition plasma membrane proteins, including functional MHC class II, from apoptotic PBMCs.
Most of us are more familiar with human or mouse neutrophils as a working system. Do you think there is anything unique about bovine neutrophils that permits them to engage in passive transfer?
PG: No, this is probably a generalized observation. There are several reasons for thinking this. First, the neutrophils interact with microparticles and apoptotic cells, which are not unique to bovine biology. Second, although we have not yet published these observations, we find similar results with neutrophils from goats. Finally, although bovine neutrophils are certainly less well-characterized than their human or mouse counterparts, no substantial differences in mechanisms of cell-trafficking, cell adhesion, or cytokine production have been identified [3 ]. However, the passive transfer mechanisms described here and in our previous manuscript [1 ] may in fact be unique to neutrophilic leukocytes, at least among cells of hematopoietic origin.
Do you have any evidence for phagocytosis leading to antigen presentation in vivo?
PG: None yet. We have detected MHC class II expression on neutrophils isolated from sites of active inflammation ex vivo, although we have not yet been able to determine with confidence whether the antigen arrived at the membrane by passive transfer or induction of mRNA expression.
As we know, massive neutrophil recruitment is a characteristic of many inflammatory responses. Can you envision a way in which passive transfer might be used therapeutically?
PG: This is certainly a critical issue. If one could remove neutrophils from peripheral blood, "load" them ex vivo via passive transfer so that they then express MHC class II and then return them, one might elicit the directed development of thymocytes into naive T cells, as well as direct the maturation of specific memory CD4+ T cells [4 ]. Extending this technology into the future, one might ultimately be capable of reducing discrimination between self and non-self, inducing immunologic tolerance.
On a more personal note, can you tell us a bit about the person who was a major influence in your professional life, and how this person helped you to choose the course your career has taken?
PG: I was most profoundly influenced by Dr. Lorne A. Babiuk, who was not only my professor in veterinary school at Western College of Veterinary Medicine (WCVM) in Saskatoon, he is also a co-author on this manuscript, and is currently the director of VIDO here where I am employed. Dr. Babiuk invited me to join his laboratory group during the summer between my 3rd and 4th years in veterinary school, during which time I worked on a project related to bovine herpesvirus-1 and latency. I learned quite a bit about the balance between host and pathogen in disease pathogenesis. More important, Dr. Babiuk served as a true mentor, as he conveyed to me his excitement about the world of science. His thoughts, ideas, and inspiration have stayed with me throughout my professional career.
When you speak of mentoring, one notes that veterinarians are not highly represented in the research community. Do you think veterinarians have a unique contribution to make to biologic research? How would you go about encouraging more veterinary students to consider research as a career?
PG: Veterinarians have unique and specific contributions to make to biologic and medical research, and toward novel therapeutic advances. There is a great deal to be learned in comparing the different biological strategies of vertebrate and invertebrate species, and considering both the conserved and the unique responses among species. Veterinarians are specifically trained to recognize differences and similarities among divergent species. When I train my students, I strongly encourage them to think in terms of evolutionary relevance, and remind them that small rodent models, while convenient, are not always the best models of human disease.
In terms of encouraging students, I feel that those of us engaged in research need to serve as mentors and role models. Each year, I speak with the first year veterinary students here at WCVM, and I try to convey my enthusiasm for my chosen field of study and my vision for the future. I sincerely want them to understand that, as veterinarians engaging in research, they will be in a position to make a most profound and long-lasting contribution to veterinary medicine and to society as a whole.
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