CXCR3 chemokine receptor contributes to specific CD8+ T cell activation by pDC during infection with intracellular pathogens.

Chemokine receptor type 3 (CXCR3) plays an important role in CD8+ T cells migration during intracellular infections, such as Trypanosoma cruzi. In addition to chemotaxis, CXCR3 receptor has been described as important to the interaction between antigen-presenting cells and effector cells. We hypothesized that CXCR3 is fundamental to T. cruzi-specific CD8+ T cell activation, migration and effector function. Anti-CXCR3 neutralizing antibody administration to acutely T. cruzi-infected mice decreased the number of specific CD8+ T cells in the spleen, and those cells had impaired in activation and cytokine production but unaltered proliferative response. In addition, anti-CXCR3-treated mice showed decreased frequency of CD8+ T cells in the heart and numbers of plasmacytoid dendritic cells in spleen and lymph node. As CD8+ T cells interacted with plasmacytoid dendritic cells during infection by T. cruzi, we suggest that anti-CXCR3 treatment lowers the quantity of plasmacytoid dendritic cells, which may contribute to impair the prime of CD8+ T cells. Understanding which molecules and mechanisms guide CD8+ T cell activation and migration might be a key to vaccine development against Chagas disease as those cells play an important role in T. cruzi infection control.

CXCR3 chemokine receptor guides Trypanosoma cruzi-specific T-cells triggered by DNA/adenovirus ASP2 vaccine to heart tissue after challenge.

CD8+ T lymphocytes play an important role in controlling infections by intracellular pathogens. Chemokines and their receptors are crucial for the migration of CD8+ T-lymphocytes, which are the main IFNγ producers and cytotoxic effectors cells. Although the participation of chemokine ligands and receptors has been largely explored in viral infection, much less is known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8+ T-lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of parasite-specific CD8+ T-cells towards infected tissues, where they may play their effector activities. Using a model of induction of resistance to highly susceptible A/Sn mice using an ASP2-carrying DNA/adenovirus prime-boost strategy, we showed that CXCR3 expression was upregulated on CD8+ T-cells, which selectively migrated towards its ligands CXCL9 and CXCL10. Anti-CXCR3 administration reversed the vaccine-induced resistance to T. cruzi infection in a way associated with hampered cytotoxic activity and increased proapoptotic markers on the H2KK-restricted TEWETGQI-specific CD8+ T-cells. Furthermore, CXCR3 receptor critically guided TEWETGQI-specific effector CD8+ T-cells to the infected heart tissue that express CXCL9 and CXCL10. Overall, our study pointed CXCR3 and its ligands as key molecules to drive T. cruzi-specific effector CD8+ T-cells into the infected heart tissue. The unveiling of the process driving cell migration and colonization of infected tissues by pathogen-specific effector T-cells is a crucial requirement to the development of vaccine strategies.

Anticardiolipin antibodies and recurrent spontaneous abortion in Brazilianwomen / Anticardiolipin antibodies and recurrent spontaneous abortion in Brazilianwomen

Aims: To determine the frequency of anti-cardiolipin antibodies (aCL) in women with previous history of recurrent spontaneous abortion (RSA).Methods: Medical records from pregnant women seen from April 2005 to December 2008 at the High-Risk Pregnancy Unit at the Hospital de Base from FUNFARME (Fundação Faculdade Regional de Medicina), in São José do Rio Preto, São Paulo, Brazil, were revised. Patients olderthan 18 years who had at least two spontaneous abortions and who were tested for aCL wereincluded in the study. Data on maternal age, number of miscarriages and the results of serological tests for aCL were recorded. The exact Fisher's test was used to compare the results. A p value less than 0.05 was considered significant.Results: During the study period a total of 294 pregnant women were seen, from whom 44 consecutive women fulfilled the inclusion criteria. The overall mean age was 33.8±5.4 years (range: 22 to 44; median: 34). Eighteen (40.9%) patients were reagent for aCL and 26 (59.1%) non-reagent,and the difference between their mean age was not statistically significant (reagent: 34.6±5.8 years; non reagent: 33.2±5.2 years, p=0.4001). Fourteen (77.8%) patients presented IgM aCL and six (33.2%), IgG aCL. Two patients (11%) were reagent for both IgM and IgG aCL. In the most of cases the aCL antibody titers were compatible with low risk for pregnancy morbidity. The number of abortions ranged from two to six. The average number of abortions among those reagent for aCL was 3.5±1.1 and in those non-reagent was 2.9±1.1 (p=0.0813). Conclusions: The frequency of aCL was elevated among patients with a history of RSA,especially those having higher number of fetal losses. Among women with at least two spontaneousabortions, the mean number of abortions was not significantly different between those reagent for aCL and those non reagent.

Objetivos: Avaliar a frequência de anticorpos anticardiolipina (aCL) em mulheres comhistória prévia de aborto espontâneo recorrente (AER).Métodos: No período de abril de 2005 a dezembro de 2008 foram avaliados os dados deprontuários de gestantes atendidas no Ambulatório de Gestação de Alto Risco do Hospital de Baseda Fundação Faculdade Regional de Medicina (FUNFARME), em São José do Rio Preto, SãoPaulo, Brasil. Foram incluídas neste estudo pacientes com idade acima de 18 anos que tiveram pelomenos dois abortos espontâneos e foram avaliadas para aCL. O teste exato de Fisher foi usado paracomparar os resultados. Valor de p menor que 0,05 foi considerado significante.Resultados: Um total de 294 mulheres gestantes foram avaliadas durante o período doestudo, das quais 44 atendiam aos critérios de inclusão. A média de idade foi 33,8±5,4 anos(variação: 22 a 44; mediana: 34). Dezoito pacientes (40,9%) foram reagentes para aCL e 26 (59,1%)não reagentes, e a diferença entre a média de idade não foi estatisticamente significante (reagentes:34,6±5,8 anos; não reagentes: 33,2±5,2 anos, p=0,4001). Quatorze (77,8%) pacientes apresentaramaCL IgM e seis (33,2%) aCL IgG. Duas pacientes (11%) foram reagentes para ambas as classes deaCL, IgM e IgG. Na maioria dos casos os títulos de anticorpos aCL foram compatíveis com baixorisco para morbidade na gravidez. O número de abortos variou de dois a seis. O número médio deabortos entre as reagentes para aCL foi de 3,5±1,1 e entre as não reagentes foi de 2,9±1,1(p=0,0813).Conclusões: A frequência de aCL foi alta entre as pacientes com história de AER,especialmente entre aquelas que tiveram um maior número de perdas fetais. Entre as mulheres compelo menos dois abortos espontâneos, a média do número de abortos não foi significativamentediferente entre aquelas reagentes e não reagentes para aCL.