immunology of infectious and parasitic diseases - XXXVII Congress ...

EXPLORING THE INFLAMMATORY ROLE OF THE MAST
CELL/KALLIKREIN-KININ CELL PATHWAY IN THE MODULATION OF T
CELL RESPONSES AGAINST TRYPANOSOMA CRUZI
BORSOI-COUTO, T. 1 ; MARIANNO-COSTA, L.J. 1 ; PESQUERO, J.B. 2 ,
SCHARFSTEIN, J. 1 ; OLIVEIRA, A.C. 1
1 Laboratório de Imunologia Molecular, IBCCF o , UFRJ, RJ. BRASIL.
2 Departamento de Biofísica, UNIFESP, SP, BRASIL.
Introduction: We have previously demonstrated that Dm28c trypomastigotes
(TCTs) activate the kinin system through activation pathways involving transcellular
cross-talk between TLR2 and Bradykinin B2 receptors (BK2R) (Monteiro
et al., 2006). Initiated by tGPI-mucin, the TLR2/CXCR2-driven inflammation
promotes the diffusion of plasma borne-kininogens to peripheral sites of
infection, allowing for downstream generation of kinins by cruzipain. Once
released in extravascular sites of infection, kinins (most likely aided by other
immunostimulory peptides) drive dendritic cell maturation via BK2R, converting
these APCs into Th1 inducers. Previous data show that B2R -/- mice succumb to
acute (systemic) T. cruzi infection. Although the susceptible phenotype was
linked to primary dysfunction of DCs, BK2R -/- mice gradually lost the ability to
generate type 1 CD4 and CD8 T cell effectors (Monteiro et al., 2007). Methods
and Results: Using the subcutaneous route of T. cruzi inoculation, here we
examined in further detail the relationship between inflammatory edema and T
cell effector function. Experiments in BK2R -/- mice showed that CCR5 was not
as strongly upregulated in CD4 T cells as in their WT counterparts. Consistent
with these findings, frequencies of intracardiac CD4 Th1 cells in infected WT
mice were significantly higher as compared to BK2R -/- . Unlike the CD8 deficient
response observed in the intraperitoneal model of infection, we found similar
frequencies of intracardiac CD8 T cells and IFNg producing CD8+ cells in
BK2R -/- and WT mice. Moreover, we did not detect differences in CTL activity
(TSKB20-splenic targets). Intriguingly, the expression of the pro-apoptotic
receptor CD95 (Fas) was not as strongly upregulated in CD8 T cells from BK2R -
/- mice as in WT. Conclusions: Our results suggest that BK2 receptor signaling
is important for the development of a Th1 response but not for CD8 T cell
response in our model of T. cruzi infection. Experiments with B1K-deficient mice
are currently being performed. Preliminar studies from our group suggest that
pharmacological intervention on the mast cell compartment (see accompanying
abstract by Nascimento et al.) may have significant impact on T cell effector
function, which will also be evaluated.