Timothy N. Bullock, Ph.D.
Associate Professor of Pathology
Telephone: (434) 982-1932
Graduate School: Thomas
Jefferson University, Philadelphia, PA
Research Interests: Generation
of vaccines to tumors
Sciences Graduate Program(s):
Immunology and Infectious Diseases
The focus of our work is on the use of
dendritic cells (DC) as immunotherapeutic vaccines against melanoma and
other malignancies. DC are extremely potent antigen presenting cells
(APC) that express MHC class I and class II molecules and an array of
costimulatory molecules that are required for the activation of naïve T
cells. Thus, DC make ideal candidates as vaccine delivery systems for
the generation of immune responses against tumors. Recent
studies have demonstrated that many patients make immune responses
against their tumors, though they usually ultimately fail to control
tumor outgrowth. Extensive investigations have identified many of
the proteins that are the targets of these immune responses, and
further defined the MHC class I and MHC class II-restricted peptides
derived from tumor antigens that are presented to cytotoxic CD8+- and
helper CD4+ T cells respectively. DC pulsed with such peptides
are the basis of the vaccines that we are currently studying.
Recent studies in our laboratory have indicated that mice immunized
with both MHC class I- and class II-restricted peptides derived from an
antigen expressed by tumor results in greater control of tumor
outgrowth as compared to mice immunized with the MHC class I-restricted
peptide alone (Hwang et al, 2007). Further studies have indicated
that tumor-specific memory CD4+ T cells enhance the activation,
differentiation and, in particular, the infiltration of tumor by
secondary CD8+ T cells. As a consequence of this, we are
1. Whether the enhanced
frequency of tumor-specific CD8+ T cells in the lungs is due to
recruitment of central memory CD8+ T cells, or the expansion of
effector memory CD8+ T cells. If recruitment is involved, which
facets of the memory CD4+ T cells are responsible, and which chemokines
and integrins are involved?
2. Is the enhanced activation and differentiation of
memory CD8+ T cells due to differential activation of DC by memory CD4+
T cells as compared to naïve CD4+ T cells?
3. Whether other parameters of CD8+ T cell function
are enhanced by coordinated reactivation with memory CD4+ T cells.
4. What are the qualitative and quantitative aspects
of memory CD4+ T cells that support secondary CD8+ T cell responses to
5. The parameters of immunization that elicit the
most potent CD4+ T cell responses, but not to the detriment of the CD8+
T cell response.
6. Whether cognate or non-cognate CD4+ T cell
responses are more supportive of tumor control when tumor is already
existent in the host.
As a consequence of our interest in how CD4+ T cells influence CD8+ T
cell responses to tumor, our lab has also shown that one of the
essential consequences of “licensing” DC via CD40-mediated stimulation
is the upregulation of the TNF-superfamily member, CD70 (Bullock,
2005). We have found that the expression of CD70 on DC is not
only a biomarker of potently activated DC, but the costimulation
rendered by CD70, via its receptor CD27 (which is expressed on most
naïve T and B cells, and a subset of NK cells) strongly influences both
CD8+ T cell and CD4+ T cell responses to DC vaccines. Current
projects in the lab involve:
1. Defining the mechanism by
which CD4+ T cells induce the expression of CD70 on DC
2. Determine which other methods of stimulating DC
induce CD70 expression on DC.
3. Examining how CD70-mediated costimulation
influences the expansion and differentiation of both CD8+ T cell and
CD4+ T cell responses.
4. Defining how to utilize CD70-mediated
costimulation to enhance immunological control of tumor.
As part of our interest in developing effective immune responses
against tumors in humans, our lab is currently studying the phenotype
and functionality of CD8+ T cell and CD4+ T cell responses elicited by
peptide+adjuvant vaccines administered to melanoma and breast cancer
patients at the University of Virginia. By understanding the
extent of activation and differentiation of the responding T cells,
both in blood and in the tumor, we hope to determine whether any
deficiencies exist in the patient’s T cell response, and whether
additional interventions may overcome such deficiencies.
• Hwang ML, Lukens JR, Bullock
TN. Cognate memory CD4+ T cells generated with dendritic cell priming
influence the expansion, trafficking, and differentiation of secondary
CD8+ T cells and enhance tumor control. J Immunol. 2007 Nov;
• Hargadon KM, Brinkman CC, Sheasley-O'neill SL,
Nichols LA, Bullock TN, Engelhard VH. Incomplete differentiation of
antigen-specific CD8 T cells in tumor-draining lymph nodes. J Immunol.
2006 Nov 1; 177(9):6081-90.
• Bullock TN, Yagita H. Induction of CD70 on
dendritic cells through CD40 or TLR stimulation contributes to the
development of CD8+ T cell responses in the absence of CD4+ T cells. J
Immunol. 2005 Jan 15; 174(2):710-7.
• PubMed Listings for this Faculty Member