[The macrophage: chief of tuberculosis immune response]. / Le macrophage: chef d'orchestre de l'immunité anti-tuberculeuse.

With nearly eight million new cases each year and two million deaths, tuberculosis (TB) remains a major health problem worldwide. The limited protection afforded by the only available vaccine, Bacille Calmette-Guerin BCG, and the emergence of multi-resistant strains to antibiotics along with the advent of AIDS, are three main causes that contributed to the increase of TB incidence during the last decade. The World Health Organization (WHO) estimates between 2000 and 2020, nearly one billion people will be newly infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, and 200 millions of them will develop the disease, of which 35 million will die if there is no improvement in controlling infection. Such improvement requires an increase in our knowledge of the fundamental biology of this very complex disease and in particular a better understanding and characterization of the types of interactions between mycobacteria and the immune system. The alveolar macrophage (MØA), the first immunological barrier that opposes the mycobacteria, plays a key role in the evolution of infection. In addition to the recognition and immediate elimination of the bacteria by phagocytosis and secretion of microbicidal products, MØA is extremely important in orchestrating the immune response and the establishment of a specific response provided by T cells. This review summarizes the state of our knowledge about the mechanisms deployed by the macrophage to contain Mtb infection with a focus on apoptosis as an innate immune response against this pathogen. We also describe the mechanisms developed by Mtb, during its coexistence with humans, in order to escape the macrophage response.

Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a.

B-chronic lymphocytic leukemia (B-CLL) cell is characterized by the accumulation of long-lived CD5+ B lymphocytes, whose survival in vivo is in part dependent on exogenous factors such as cytokines and/or extracellular matrix proteins. Homeostatic chemokines are critical mediators of lymphoid cell trafficking. However, how they function in cell signaling and survival remains ill-defined. In this study, we have investigated the role of the homeostatic chemokines, CXCL12, CCL21, CCL19 and CXCL13, in B-CLL cell survival. Using primary leukemic cells isolated from 26 patients, we observed that each chemokine enhances cell survival. Chemokines induced the phosphorylation of ERK1/2 and p90RSK, and of Akt and its effectors GSK3 and FOXO3a. Consistently, inhibitors against mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase inhibited chemokine-induced survival. Moreover, using a constitutively active mutated form of FOXO3a or siRNAs against FOXO3a in transfection experiments performed in primary B-CLL cells, we directly demonstrated the critical role of FOXO3a in both spontaneous and chemokine-induced B-CLL cell survival. Overall, our data support the notion that homeostatic chemokines contribute to B-CLL resistance to cell death through inactivation of the transcription factor FOXO3a, which may represent a novel therapeutic target in this hematopoietic malignancy.

An isoleucine-based allosteric switch controls affinity and shape shifting in integrin CD11b A-domain.

In response to cell activation signals, integrins switch from a low to a high affinity state. Physiologic ligands bind to integrins through a von Willebrand Factor A-type domain. Crystallographic studies revealed two conformations of this domain, "closed" and "open." The latter crystallizes in complex with a pseudoligand or ligand, suggesting that it represents the high affinity state; data linking structure and activity are lacking however. In this communication, we expressed stable low and high affinity forms of integrin CD11b A-domain and determined their binding isotherms and crystal structures. The low affinity form, generated by deleting an N-terminal extension extrinsic to the domain, did not bind to physiologic ligands, and crystallized in the closed conformation. The high affinity form was generated by either deleting or substituting an invariable C-terminal Ile(316), wedged into a hydrophobic socket in the closed form, but displaced from it in the open structure. Both mutants crystallized in the open conformation, and the Ile(316) --> Gly-modified integrin displayed high affinity. Structural differences between the low and high affinity forms were detected in solution. These data establish the structure-function correlates for the CD11b A-domain, and define a ligand-independent isoleucine-based allosteric switch intrinsic to this domain that controls its conformation and affinity.