Martha Alexander-Miller
Associate Professor of Microbiology and Immunology

B.S., 1988  (Zoology)  Butler University
Ph.D., 1993  (Immunology)  Washington University  

My laboratory is interested in understanding the activation and regulation of CD8⁺ cytolytic T lymphocytes during the course of viral infections. A number of cell surface molecules and environmental influences are known to be involved in the activation of these cells; however, many aspects of precisely how these interactions contribute to the regulation and resultant functional phenotype of CTL are unknown. The repertoire of CTL specific for a particular peptide antigen can encompass a broad range of sensitivity to peptide antigen, termed avidity. In recent work using a TCR transgenic model system, we have found that avidity can be controlled by the isoform of CD8 expressed (αα homodimers versus αβ heterodimers). Expression of the αβ heterodimeric form of CD8 promotes co-localization of CD8 with the TCR facilitating optimal TCR signaling and thus activation.  Current studies focus on understanding the control of CD8 expression and the effect of CD8 on the formation of the immunological synapse.

A second area of investigation is the generation of CD8⁺ T cells of high versus low avidity following respiratory tract infection.  We have found that there is a kinetic separation in the activation/expansion of high and low avidity cells with high avidity cells selectively elicited early following infection.  As high avidity cells are known to be a critical component of an optimal anti-viral response, current studies are aimed at identifying the mechanisms responsible for selective activation of high avidity cells.  Information gained may lead to the design of improved vaccines that will be optimal for elicitation of high avidity cells.

Another ongoing project in the lab focuses on the regulation of virus-specific effector cells in the lung environment following respiratory infection with the paramyxovirus simian virus 5 (SV5).  In these studies we have found that CD8⁺ T cells present in the lung lose function over time.  This is a surprising finding given that these cells are present at the site of virus clearance.  Studies are underway to determine the mediator responsible for this effect.

Finally we have made the observation that respiratory infection with high doses of vaccinia virus (a model for smallpox) results in a reduced CD8⁺ T cell response.  This effect is selective to the lung environment as immunization by other routes with the same dose of virus is not detrimental to the generation of CD8⁺ T cells. The focus of current studies is to understand the basis for the reduced response following respiratory infection.  The findings from these studies may lead to the design of improved immunotherapeutics.

Recent Publications (selected):

Gray, P.M., G.D. Parks, and M.A. Alexander-Miller. 2005. Modulation of CD8⁺ T cell avidity by increasing the turnover of viral antigen during infection. Cell. Immunol 231:14.

Alexander-Miller, M.A. 2005. High avidity CD8⁺ T cells: Optimal soldiers in the war against viruses and tumors. 2004. Immunol.Res. 31: 13-24.

Gray, P.M., S. Arimilli, E.M. Palmer, G.D. Parks and M.A. Alexander-Miller. 2005. Altered function in CD8⁺ T cells following Paramyxovirus infection of the respiratory tract. J. Virol. 79:3339

Pejawar, S., G.D. Parks, and M.A. Alexander-Miller. 2005. Abortive versus productive viral infection of dendritic cells with a Paramyxovirus results in differential upregulation of select costimulatory molecules. J. Virol. in press.