CD44loCD62Lhi regulatory T cells preferentially access IL-2 in T cell zones due to expression of CCR7

SUMMARY Foxp3+ regulatory T (Treg) cells limit inflammatory responses and maintain immune homeostasis. Although comprised of several phenotypically and functionally distinct subsets, the differentiation of specialized Treg cell populations within the periphery is poorly characterized. We demonstrate that the development of T-bet+ Treg cells that potently inhibit T helper (Th)1 cell responses was dependent on the transcription factor STAT1, and occurred directly in response to interferon-γ produced by effector T cells. Additionally, delayed induction of the IL-12Rβ2 receptor component following STAT1 activation helped ensure that Treg cells do not readily complete STAT4-dependent Th1 cell development and lose their ability to suppress effector T cell proliferation. Thus, we define a pathway of abortive Th1 cell development that results in the specialization of peripheral Treg cells, and demonstrate that impaired expression of a single cytokine receptor helps maintain Treg cell suppressive function in the context of inflammatory Th1 cell responses.

Summary Regulatory T (Treg) cells play a vital role in the prevention of autoimmunity and the maintenance of self-tolerance but also have an active role in inhibiting immune responses during viral, bacterial and parasitic infections. Whereas excessive Treg activity can lead to immunodeficiency, chronic infection and cancer, too little Treg activity results in autoimmunity and immunopathology, and impairs the quality of pathogen-specific responses. Recent studies have helped define the homeostatic mechanisms that support the diverse pool of peripheral Treg cells under steady-state conditions, and delineate how the abundance and function of Treg cells changes during inflammation. These findings are highly relevant for developing effective strategies to manipulate Treg cell activity to promote allograft tolerance and treat autoimmunity, chronic infection and cancer.

Pseudomonas aeruginosa is an important opportunistic human pathogen that lives in biofilm-like cell aggregates at sites of chronic infection, such as those that occur in the lungs of patients with cystic fibrosis and nonhealing ulcers. During growth in a biofilm, P. aeruginosa dramatically increases the production of filamentous Pf bacteriophage (Pf phage). Previous work indicated that when in vivo Pf phage production was inhibited, P. aeruginosa was less virulent. However, it is not clear how the production of abundant quantities of Pf phage similar to those produced by biofilms under in vitro conditions affects pathogenesis. Here, using a murine pneumonia model, we show that the production of biofilm-relevant amounts of Pf phage prevents the dissemination of P. aeruginosa from the lung. Furthermore, filamentous phage promoted bacterial adhesion to mucin and inhibited bacterial invasion of airway epithelial cultures, suggesting that Pf phage traps P. aeruginosa within the lung. The in vivo production of Pf phage was also associated with reduced lung injury, reduced neutrophil recruitment, and lower cytokine levels. Additionally, when producing Pf phage, P. aeruginosa was less prone to phagocytosis by macrophages than bacteria not producing Pf phage. Collectively, these data suggest that filamentous Pf phage alters the progression of the inflammatory response and promotes phenotypes typically associated with chronic infection.

SUMMARY Thymically derived Foxp3+ regulatory T (Treg) cells have a propensity to recognize self-peptide:MHC complexes, but their ability to respond to epitope-defined foreign antigens during infectious challenge has not been demonstrated. Here we show that pulmonary infection with Mycobacterium tuberculosis (Mtb), but not Listeria monocytogenes (Lm), induced robust lymph node expansion of a highly activated population of pathogen-specific Treg cells from the pre-existing pool of thymically derived Treg cells. These antigen-specific Treg cells peaked in numbers 3 weeks after infection but subsequently underwent selective elimination driven, in part, by interleukin-12-induced intrinsic expression of the Th1-cell-promoting transcription factor T-bet. Thus, the initial Mtb-induced inflammatory response promotes pathogen-specific Treg cell proliferation, but these cells are actively culled later, probably to prevent suppression during later stages of infection. These findings have important implications for the prevention and treatment of tuberculosis and other chronic diseases in which antigen-specific Treg cells restrict immunity.

Macrophages present early in inflammation are functionally distinct from those at later stages. The predominant macrophage phenotype must transition from pro-inflammatory to pro-reparative to facilitate wound healing and scar resolution. If macrophages fail to acquire a tissue-healing phenotype, dysregulated signals can be drivers of disease processes, such as sustained, exuberant inflammation-as occurs in arthropathies-and fibrosis. Comprehensive understanding of the roles of specific macrophage populations at different stages of the repair process will support the development of immune-targeted therapies for diseases such as fibrosis.

Several members of the matrix metalloproteinase (MMP) family control a range of immune processes, such as leukocyte influx and chemokine activity. Stromelysin-2 (MMP10) is expressed by macrophages in numerous tissues after injury; however, little is known of its function. Here, we report that MMP10 is expressed by macrophages in human lungs from patients with cystic fibrosis and induced in mouse macrophages in response to Pseudomonas aeruginosa infection both in vivo and by isolated resident alveolar and bone marrow-derived macrophages (BMDM). Our data indicates that macrophage MMP10 serves a beneficial function in response to acute infection. Whereas wildtype mice survived infection with minimal morbidity, 50% of Mmp10−/− mice died and all showed sustained weight loss (morbidity). Although bacterial clearance and neutrophil influx did not differ between genotypes, macrophage numbers were about 3-fold greater in infected Mmp10−/− lungs than in wildtypes. Adoptive transfer of wildtype BMDM normalized infection-induced morbidity in Mmp10−/− recipients to wildtype levels demonstrating that the protective effect of MMP10 was due to its production by macrophages. Both in vivo and in cultured alveolar macrophages and BMDM, expression of several M1 macrophage markers was elevated, while M2 markers were reduced in Mmp10−/− tissue and cells. Global gene expression analysis revealed that infection-mediated transcriptional changes persisted in Mmp10−/− BMDM long after they were down-regulated in wildtype cells. These results indicate that MMP10 serves a beneficial role in response to acute infection by moderating the pro-inflammatory response of resident and infiltrating macrophages.

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