of the Max - MDC

Regulatory Mechanisms of
Lymphocyte Trafficking in
Homeostasis and
Immunopathogenesis
Uta E. Höpken
(Helmholtz Fellow)
Regulated lymphocytic recirculation is pivotal in immune system homeostasis and immunopathogenesis.
Our work is focused on the role of the chemokine/chemokine receptor system in homeostatic
lymphocytic recirculation, systemic and mucosal immune responses, and lymphoid neo-organogenesis
during chronic inflammatory or infectious diseases. We further focus on the molecular
mechanisms of immune surveillance in preclinical mouse models for B cell lymphoma.
Lymphocytic homeostasis and adaptive immunity
CCR7 regulates peripheral homeostatic lymphocyte
recirculation and mucosal tissue integrity
We have been able to demonstrate that CCR7 controls homeostatic
recirculation of lymphocytes through non-lymphoid
tissues. Lack of CCR7 resulted in a massive accumulation of
B and T lymphocytes in body cavities and epithelial tissues
of CCR7-deficient mice. In the gastrointestinal tract, lymphocytes
accumulated and formed functional lymphoid follicles.
Moreover, lack of CCR7 induces age-dependent histomorphological
changes in the stomach resulting in a severe
hypertrophic gastropathy resembling Menetrier’s disease.
Thus, CCR7 is ultimately required for the maintenance of
homeostatic lymphocyte recirculation and tissue egress. We
are currently exploring the cellular and molecular mechanisms
underlying the development of the aberrant ectopic
follicles and hypertrophic gastropathy in CCR7 -/- mice.
Additionally, we are investigating the role of homeostatic
chemokines in the development of tertiary lymphoid tissues
during chronic inflammatory processes, e.g. in Helicobacter
pylori-induced mucosa-associated lymphoid tissue (MALT)
lymphoma and autoimmmune diseases.
Distinctive role of CCR7 in cytotoxic T cell priming
and in the functional activity of naive- and effector/memory-like
regulatory T cells
(in cooperation with M. Kursar, H.-W. Mittrücker, and
S.H.E. Kaufmann, MPI for Infectious Biology, Berlin)
To dissect the role of CCR7 in T cell activation and differentiation
in the process of adaptive immune responses, we analyzed
microbial-specific cytotoxic CD8+ T cell responses. We
found that the activation of naive MHC class Ia-restricted
CD8+ T cells after L. monocytogenes-infection markedly
depends on CCR7. In contrast, MHC class Ib-restricted CD8+
T cells and MHC class II-restricted CD4+ T cells showed only
some dependency on CCR7. Consequently, different T cell
subtypes and maturation stages have discrete requirements
for CCR7 during primary and secondary L. monocytogenesinfection.
(in cooperation with A. Menning, A. Hamann, and
J. Hühn, DRFZ, Berlin)
Naive-like and effector/memory-like regulatory T cell subsets
express CCR7. Lack of CCR7 expression causes a strongly
hampered migration of Tregs into lymph nodes accompanied
by a severely reduced capacity to suppress antigen-induced
naive T cell proliferation in mice. Thus, CCR7 critically determines
Treg in vivo function by mediating their appropiate
tissue localiziation.
Immunosurveillance and interactions between
tumor cells and its microenvironment
(in cooperation with A. Rehm, I. Anagnostopoulos,
H. Stein, and B. Dörken, MDC, Charité, Berlin)
As a paradigm for tumor cell and stroma interactions, we
have focused on the primary mediastinal B cell lymphoma
(PMBL). By taking advantage of the chemokine system, we
assessed functionally and phenotypically the relationship
between PMBL and their supposed ancestors, thymic B cells,
and secondly, we compared the chemokine/chemokine
receptor expression profile of PMBL with other NHL and cHL.
The recruitment and trapping of neoplastic cells to and
within the extranodal location in PMBL could be correlated
with a specific chemokine/chemokine receptor expression
profile. We have identified an abundant expression and
functionality of the classical homeostatic chemokine receptors
and their ligands within PMBL and cell lines derived
thereof. In contrast, CCR6 and CCR9, both considered as
homeostatic and inflammatory receptors, exhibit a differential
expression pattern when we compared primary PMBL
lesions, tumor cell lines, and their putative ancestors,
thymic B cells. Taken together, the abundant co-expression
of homeostatic chemokine receptors in PMBL in all likeli-
Cancer Research 121