Novel role for IL-22 in protection during chronic Mycobacterium tuberculosis HN878 infection.

Approximately 2 billion people are infected with Mycobacterium tuberculosis (Mtb), resulting in 1.4 million deaths every year. Among Mtb-infected individuals, clinical isolates belonging to the W-Beijing lineage are increasingly prevalent, associated with drug resistance, and cause severe disease immunopathology in animal models. Therefore, it is exceedingly important to identify the immune mechanisms that mediate protection against rapidly emerging Mtb strains, such as W-Beijing lineage. IL-22 is a member of the IL-10 family of cytokines with both protective and pathological functions at mucosal surfaces. Thus far, collective data show that IL-22 deficient mice are not more susceptible to aerosolized infection with less virulent Mtb strains. Thus, in this study we addressed the functional role for the IL-22 pathway in immunity to emerging Mtb isolates, using W-Beijing lineage member, Mtb HN878 as a prototype. We show that Mtb HN878 stimulates IL-22 production in TLR2 dependent manner and IL-22 mediates protective immunity during chronic stages of Mtb HN878 infection in mice. Interestingly, IL-22-dependent pathways in both epithelial cells and macrophages mediate protective mechanisms for Mtb HN878 control. Thus, our results project a new protective role for IL-22 in emerging Mtb infections.

Interleukin-17-dependent CXCL13 mediates mucosal vaccine-induced immunity against tuberculosis.

The variable efficacy of tuberculosis (TB) vaccines and the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) emphasize the urgency for not only generating new and more effective vaccines against TB but also understanding the underlying mechanisms that mediate vaccine-induced protection. We demonstrate that mucosal adjuvants, such as type II heat labile enterotoxin (LT-IIb), delivered through the mucosal route induce pulmonary Mtb-specific T helper type 17 (Th17) responses and provide vaccine-induced protection against Mtb infection. Importantly, protection is interferon-γ (IFNγ)-independent but interleukin-17 (IL-17)-dependent. Our data show that IL-17 mediates C-X-C motif chemokine ligand 13 (CXCL13) induction in the lung for strategic localization of proinflammatory cytokine-producing CXCR5+ (C-X-C motif chemokine receptor 5-positive) T cells within lymphoid structures, thereby promoting early and efficient macrophage activation and the control of Mtb. Our studies highlight the potential value of targeting the IL-17-CXCL13 pathway rather than the IFNγ pathway as a new strategy to improve mucosal vaccines against TB.

LAIR2-expressing extravillous trophoblasts associate with maternal spiral arterioles undergoing physiologic conversion.

Leukocyte-associated immunoglobulin-like receptor 2 (LAIR2) was identified on a global gene expression microarray analysis of surplus chorionic villus sampling (CVS) tissues as down-regulated in the first trimester of preeclampsia pregnancies. LAIR2 is the soluble receptor counterpart to LAIR1, an inhibitory receptor found on multiple immune cell subsets. In situ and immunohistochemical studies have previously shown that placental expression of LAIR2 expression is highly restricted, confined to the more distal portions of extravillous trophoblast (EVT) cell columns. This study examines LAIR2 expression in deeper layers of trophoblasts in the placental implantation site, maternal decidua and maternal spiral arterioles. Immunohistochemical staining detected LAIR2 expression on a subset of EVT within the implantation site. This trophoblast included the invasive EVT infiltrating the maternal decidual vessels and the EVT forming the endovascular trophoblastic plugs. More specifically, LAIR2-positive EVT showed a striking predilection for maternal decidual arterioles and the immediately surrounding decidua. Moreover, the appearance of EVT expressing LAIR2 in these areas was contemporaneous with the process of spiral arteriole remodeling. Based on these findings, we suggest that LAIR2-expressing EVT may play an important role in the remodeling of maternal spiral arterioles.

LAIR2 localizes specifically to sites of extravillous trophoblast invasion.

PURPOSE: A global gene expression microarray analysis of surplus chorionic villus sampling (CVS) tissues identified leukocyte-associated immunoglobulin-like receptor 2 (LAIR2) as down-regulated in the first trimester of pregnancies destined for preeclampsia. Neither the localization nor the function of LAIR2 has been examined in the placenta. Localization studies were conducted in placental tissues to determine the precise sites of LAIR2 mRNA production and protein binding. RESULTS: Quantitative real time polymerase chain reaction (qRT-PCR) indicated LAIR2 expression in CVS, but none in breast, lymph node, kidney, skin, uterus, or third trimester placentas. In situ hybridization (ISH) revealed a highly restricted LAIR2 localization. LAIR2 mRNA was found only in the more distal portions of trophoblast anchoring cell columns, adjacent to the invading extravillous trophoblast (EVT). Immunohistochemistry (IHC) detected intracellular LAIR2 staining in these same cells. Extracellular staining of this soluble receptor was found in the acellular material between invasive EVT cells distal to the anchoring cell columns. CONCLUSIONS: ISH and IHC staining for LAIR2 detected specific, highly localized expression at the leading edge of EVT anchoring cell columns in first trimester placentas. This staining likely identifies the site of production for this soluble receptor. Following secretion, the receptor appears to bind extracellular material among the invasive EVT. The precise restriction of this protein only to the sites of EVT invasion strongly suggests that it functions to regulate this invasion. The decreased LAIR2 expression noted in first trimester placentas that ultimately developed preeclampsia further suggests that alterations in LAIR2 may play an etiologic role in preeclampsia.