CURRENT PERSONNEL:
Rebecca L. O'Brian, P.I.
Christina Roark, Instructor
M. Kemal Aydintug, Research Associate
Jena French, Postdoctoral Fellow
Xiang Yin, Laboratory Technician

COLLABORATORS:
Willi Born, Ph.D. (National Jewish)
John Kappler, Ph.D. (National Jewish)
Sally Huber, Ph.D. (Univ. of Vermont)

RESEARCH INTERESTS:
My research concerns the specificity and function of the γδ T lymphocytes. These cells represent a relatively rare type of T cell in mice and humans whose purpose is at this time not clear. Other lymphocytes, αβ T cells and B lymphocytes, act to detect and eliminate foreign micro-organisms from the body. They are able to do this because of their ability to distinguish foreign molecules from the normal ones produced by our own bodies. This ability is conferred by the presence on each individual lymphocyte of a unique cell membrane receptor, which undergoes a screening process during the cell's development, to ensure that it will not bind to self molecules, while retaining the potential to bind to a foreign molecule. For example, αβ T cells each carry a unique T cell receptor (TCR), which if it should happen to bind to a portion of a foreign protein carried by an infected cell, will then deliver an activating signal to the interior of the cell, causing the T cell not only to undergo replication and make many copies of itself, but also to produce factors that lead to the destruction of the cell that triggered the response. The γδ T cells also have TCRs on their cell membranes, which are related but distinct from those carried by αβ T cells. A growing body of evidence now indicates that γδ TCRs, instead of recognizing foreign molecules, rather see molecules that are produced by our own bodies, whose production is induced during infection or inflammation. The value of having this type of self-reactive lymphocyte is not yet clear, but several studies indicate that γδ T cells may play a regulatory role in inflammation. Controversial findings as to the type of role they play may be explained if one considers γδ T cells as a group of different subsets having distinct functions. The subsets are defined by the expression in their TCR of particular Vγs or Vγ/Vδ combinations. In the mouse, we have found that in three different disease models in mice, the functional role of certain γδ T cell subsets appears to be constant. Moreover, we have recently shown that at least two of these subsets also differ from one another in their tendency to undergo homeostatic proliferation, which also suggests subset-based functional differences. Projects are now underway to further define the functional roles of the mouse Vγ 1-, Vγ 4-, and Vγ 6-expressing γδ T cell subsets during disease, determine the mechanisms by which the functions are carried out, and ascertain how the subsets become activated.

Since the self-produced molecules which stimulate γδ T cells have in most cases not yet been defined, the nature of the ligands for the γδ TCR remains a major question in the field. It is critical not only to understanding how these cells function, but may also be key to manipulating γδ T cells for use therapeutically. To get at this question, we generated multimeric versions of recombinant soluble γδ TCRs, and have recently shown that these can be used like monoclonal antibodies as reagents to detect their own ligands. Our initial findings using three such soluble γδ TCR multimers indicated that the natural ligands are cell surface molecules present on certain epithelial cells, and are either themselves proteins or are protein-associated. Work towards the purification and identification of natural ligands of γδ TCRs is now underway. We expect that these soluble γδ TCRs multimers will be invaluable in unequivocally identifying the ligands.

Selected Bibliography

• Aydintug, M. K., C. L. Roark, X. Yin, J. M. Wands, W. K. Born, and R. L. O'Brien. 2004. Detection of cell surface ligands for the γδ TCR using soluble TCRs. J. Immunol. In press.
• O'Brien, R. L., M. L. Lahn, W. K. Born, and S. A. Huber. 2001. TCR and function co-segregate in γδ T cell subsets. Chemical Immunology: γδ T cells. Karger, Basel Ed. A. Takashima and P. Bergstresser:1-28.
• Huber, S. A., D. A. Graveline, W. K. Born, and R. L. O'Brien. 2001. Cytokine production by Vγ + T cell subsets is an important factor determining CD4 Th-cell phenotype and susceptibility of BALB/c mice to coxsackievirus B3-induced myocarditis. J. Virol. 75:5860-5869.
• Huber, S. A., D. Graveline, M. K. Newell, W. K. Born, and R. L. O'Brien. 2000. Vγ 1+ T cells suppress and Vγ 4+ T cells promote susceptibility to coxsackievirus B3-induced myocarditis in mice. J. Immunol. 165:4174-4181.
• Mukasa, A., W. K. Born, and R. L. O'Brien. 1999. Inflammation alone evokes the response of a TCR-invariant mouse γδ T cell subset. J. Immunol. 162:4910-4913.

LINKS

Willi Born, National Jewish Medical and Research Center: www.njc.org/faculty/born.html

View of Recent Publications in PubMed