Abstracts (complete list) - Wissenschaft Online

Wiebke Hartmann, Markus M. Simon, Bernhard Fleischer, Simone Korten
A new role for granzymes: Suppression of defence against
helminths
Granzyme (gzm) A and B are major cytotoxic serine proteases of NK cells and cytotoxic
T cells, known to play a key role in the destruction of tumor cells or infected cells.
Recent studies show that gzmB is released by regulatory T (Treg) cells suppressing
effector T cells, antigen-presenting cells, B and NK cells. On the other hand, gzmA and
B can facilitate leukocyte migration by degrading extracellular matrix proteins. Their
role in helminth infection has not been examined so far. As CD4+ T cells, NK cells, B
and Treg cells affect the mixed Th1/Th2 (Th2-biased) immune defence against filariae,
conferred substantially by granulocytes, we investigated the role of gzmA and B during
infection of mice with the rodent filaria Litomosoides sigmodontis. Resistant wildtype
C57BL/6 (wt) mice (infection is finished before worms reach sexual maturity) and
gzmAxB knock out (ko) mice, generated on this background, were naturally infected via
mites. GzmAxB ko mice harboured a lower worm load in the pleural cavity than wt mice
in the early and late phase of infection rendering them hyperresistant. This lower worm
load in ko mice was associated with early reduction of NK and apoptotic cells and a
reduction of Th1 specific IgG2b, but increase of pleural IL-5 compared to wt mice.
Pleural Foxp3+CD4+ Treg cells were detectable early with numbers unaffected by gzmA
or B deficiency and declining with infection. GzmAxB deficiency did not generally
influence leukocyte migration, as size and proportions of leukocyte subpopulations were
unaltered. Therefore, we conclude that a pronounced Th2 response in gzmAxB deficient
mice induced by a still unclear way leads to hyperresistance in this filarial infection and
indicates for the first time a defence-suppressive role of granzymes in an infection.